ABL1

Gene Summary

Gene:ABL1; ABL proto-oncogene 1, non-receptor tyrosine kinase
Aliases: ABL, JTK7, p150, c-ABL, v-abl, CHDSKM, c-ABL1, BCR-ABL, bcr/abl
Location:9q34.12
Summary:This gene is a protooncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of the protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene. The ubiquitously expressed protein has DNA-binding activity that is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function. This gene has been found fused to a variety of translocation partner genes in various leukemias, most notably the t(9;22) translocation that results in a fusion with the 5' end of the breakpoint cluster region gene (BCR; MIM:151410). Alternative splicing of this gene results in two transcript variants, which contain alternative first exons that are spliced to the remaining common exons. [provided by RefSeq, Aug 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tyrosine-protein kinase ABL1
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (48)
Pathways:What pathways are this gene/protein implicaed in?
Show (6)

Cancer Overview

Alterations of the ABL1 protooncogene by chromosomal rearrangements, particularly t(9;22) translocations, or by viral transductions are implicated in haematological malignancies. The t(9;22) translocation is present in over 90% of chronic myelogeneous leukaemia cases. This translocation causes the "head to tail" fusion of the BCR and ABL genes. t(9;22) translocations are also present (though less common) in acute lymphoblastic leukaemia.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Protein Tyrosine Phosphatases
  • Transduction
  • Protein Kinase Inhibitors
  • Ubiquitin-Protein Ligases
  • Whole Exome Sequencing
  • Protein Methyltransferases
  • BCR
  • Cell Surface Receptors
  • RT-PCR
  • Primary Myelofibrosis
  • Triazoles
  • Withholding Treatment
  • Myelodysplastic Syndromes
  • Chronic Myelogenous Leukemia
  • Fusion Proteins, bcr-abl
  • Messenger RNA
  • Acute Lymphocytic Leukaemia
  • Cancer RNA
  • Sequence Analysis, RNA
  • Oncogene Fusion Proteins
  • Watchful Waiting (Prostate Ca)
  • STAT5 Transcription Factor
  • Remission Induction
  • Tumor Microenvironment
  • RNA
  • Research
  • PPARG
  • Young Adult
  • BRAF
  • Translocation
  • Philadelphia Chromosome
  • Nucleic Acid Amplification Techniques
  • Transfection
  • Chromosome 9
  • Transcription
  • DNA Sequence Analysis
  • ABL1
  • Homologous Transplantat
  • Survival Rate
  • Sensitivity and Specificity
  • Recurrence
  • Syria
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Acute Lymphocytic Leukaemia (ALL)NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies, with a frequency of 5% in T-cell ALL. (De Braekeleer et al, 2011)
View Publications52
Chronic Myelogenous LeukemiaBCR-ABL Translocation in Chronic Myeloid Leukaemia
The t(9;22)(q34;q11) "Philadelphia" translocation is characteristic of chronic myeloid leukaemia (CML). The translocation results in the "head to tail" fusion of the BCR and ABL1 genes and is present in over 90% of CML cases.
See: More details below...
Acute Lymphocytic Leukaemia (ALL)BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
See: More details below...

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

BCR-ABL Translocation in Chronic Myeloid Leukaemia

The t(9;22)(q34;q11) "Philadelphia" translocation is characteristic of chronic myeloid leukaemia (CML). The translocation results in the "head to tail" fusion of the BCR and ABL1 genes and is present in over 90% of CML cases.

See also: Chronic Myeloid Leukemia (CML) - Clinical and Research information
See also: BCR.htm gene

Latest Publications

Millett R, Aggarwal A, Tabbara I, Nassereddine S
Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.
Anticancer Res. 2019; 39(8):4333-4335 [PubMed] Related Publications
Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.

Massimino M, Stella S, Tirrò E, et al.
Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3
Anticancer Res. 2019; 39(7):3949-3954 [PubMed] Related Publications
We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.

Tirrò E, Massimino M, Stella S, et al.
Efficacy of Nilotinib in a CML Patient Expressing the Three-way Complex Variant Translocation t(2;9;22).
Anticancer Res. 2019; 39(7):3893-3899 [PubMed] Related Publications
BACKGROUND/AIM: Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or second-generation tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients.
CASE REPORT: We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib.
CONCLUSION: CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.

Xu J, Wu M, Zhu S, et al.
Detecting the stable point of therapeutic effect of chronic myeloid leukemia based on dynamic network biomarkers.
BMC Bioinformatics. 2019; 20(Suppl 7):202 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Most researches of chronic myeloid leukemia (CML) are currently focused on the treatment methods, while there are relatively few researches on the progress of patients' condition after drug treatment. Traditional biomarkers of disease can only distinguish normal state from disease state, and cannot recognize the pre-stable state after drug treatment.
RESULTS: A therapeutic effect recognition strategy based on dynamic network biomarkers (DNB) is provided for CML patients' gene expression data. With the DNB criteria, the DNB with 250 genes is selected and the therapeutic effect index (TEI) is constructed for the detection of individual disease. The pre-stable state before the disease condition becomes stable is 1 month. Through functional analysis for the DNB, some genes are confirmed as key genes to affect the progress of CML patients' condition.
CONCLUSIONS: The results provide a certain theoretical direction and theoretical basis for medical personnel in the treatment of CML patients, and find new therapeutic targets in the future. The biomarkers of CML can help patients to be treated promptly and minimize drug resistance, treatment failure and relapse, which reduce the mortality of CML significantly.

Sheng Y, Ji Z, Zhao H, et al.
Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells.
Cell Prolif. 2019; 52(4):e12611 [PubMed] Related Publications
OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.
MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34
RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.
CONCLUSIONS: Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

Luo N, Xia Q, Zhang L, et al.
One-step discrimination of BCR/ABL
Anal Chim Acta. 2019; 1067:129-136 [PubMed] Related Publications
BCR/ABL

Kizilors A, Crisà E, Lea N, et al.
Effect of low-level BCR-ABL1 kinase domain mutations identified by next-generation sequencing in patients with chronic myeloid leukaemia: a population-based study.
Lancet Haematol. 2019; 6(5):e276-e284 [PubMed] Related Publications
BACKGROUND: Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. Next-generation sequencing (NGS) allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated. We aimed to examine the clinical effects of low-level kinase domain mutations identified using NGS in patients with chronic myeloid leukaemia.
METHODS: In this population-based study, we included consecutive patients newly diagnosed with chronic myeloid leukaemia treated with first-line tyrosine kinase inhibitors, and patients identified at the time of resistance to first-line treatment with imatinib at six institutions (teaching hospitals and district hospitals) in southeast England. We screened patients for BCR-ABL1 kinase domain mutations using NGS, irrespective of patient response to tyrosine kinase inhibitor therapy. When we detected a mutation with NGS, we retrospectively analysed all previous samples to establish the date of first occurrence and subsequent kinetics of the mutant subclone (or subclones). The primary endpoints of this study were progression-free and event-free survival at 5 years.
FINDINGS: Between Feb 1, 2007, and Dec 31, 2014, we screened 121 patients with chronic myeloid leukaemia for BCR-ABL1 kinase domain mutation. 99 consecutive patients were newly diagnosed, with available sequential RNA stored. The remaining 22 patients were diagnosed between June 1, 1999, and June 30, 2006, and were screened at the time of resistance to first-line treatment with imatinib. Imatinib was the first-line treatment for 111 patients, nilotinib for seven patients, and dasatinib for three patients. We detected a kinase domain mutation in 25 (21%) of 121 patients. Low-level kinase domain mutations were first identified in 17 (68%) of 25 patients with mutation. For patients with a complete cytogenetic response, 13 (14%) of 93 patients screened had a mutation. Five (71%) of the seven patients with a clinically relevant mutation lost complete cytogenetic response compared with 15 (17%) of 86 patients without a clinically relevant mutation (80 patients without mutation and six patients with a tyrosine kinase inhibitor-sensitive mutation, p=0·0031). Patients harbouring a mutant clone had poorer 5-year progression-free survival (65·3% [95% CI 40·5-81·8] vs 86·9% [75·8-93·2]; p=0·0161) and poorer 5-year event-free survival (22·2% [CI 5·6-45·9] vs 62·0% [50·4-71·6]; p<0·0001) than did patients without a mutation. We identified a kinase domain mutation in four (10%) of 41 patients with samples available at 3 months after starting first-line tyrosine kinase inhibitor treatment; all four subsequently progressed to accelerated phase disease compared with only three (8%) of 37 without a mutation (p<0·0001).
INTERPRETATION: NGS reliably and consistently detected early appearance of kinase domain mutations that would not otherwise be detected by Sanger sequencing. For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications. NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care.
FUNDING: None.

Vatanmakanian M, Tavallaie M, Ghadami S
Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?
Cell Commun Signal. 2019; 17(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the current study, we aimed to query if the gene regulation of CCN3 is mediated by the promoter methylation in the patients with CML. In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia.
METHODS: To address this issue, we applied bisulfite-sequencing technique as a high-resolution method to study the regulatory segment of the CCN3 gene. The results were analyzed in newly diagnosed CML patients as well as following imatinib therapy. We also evaluated the correlation of CCN3 promoter methylation with BCR-ABL1 levels.
RESULTS: Our findings revealed that the methylation occurs frequently in the promoter region of CML patients showing a significant increase of the methylated percentage at the CpG sites compared to normal individuals. Interestingly, this hypermethylation was indicated to be independent of BCR-ABL1 titers in both groups, which might suggest a mechanism beyond the BCR-ABL1 function.
CONCLUSION: Despite suggesting that the CCN3 hypermethylation acts as a molecular mechanism independent of BCR-ABL1 function in CML patients, this scenario requires further validation by complementary experiments. In the case of acting upstream of BCR-ABL1 signaling, the methylation marker can provide early detection and a novel platform for targeted epigenetic modifiers for efficient treatment in imatinib resistant patients.

Sazawal S, Chhikara S, Singh K, et al.
Distribution of common BCR-ABL fusion transcripts and their impact on treatment response in Imatinib treated CML patients: A study from India.
Indian J Pathol Microbiol. 2019 Apr-Jun; 62(2):256-260 [PubMed] Related Publications
Background: Philadelphia chromosome (Ph): Hallmark of CML is caused by reciprocal translocation between chromosomes 9 and 22 resulting in BCR-ABL fusion protein. Most commonly associated breakpoint with CML is M-bcr in exon 13 or exon 14, producing splice variant b2a2 or b3a2 respectively. The distribution of these transcripts and their influence on clinico-hematological parameters is variable. Impact of the fusion transcripts on treatment outcome in Imatinib treated CML patients is still a matter of debate.
Aims/settings and design: We conducted this study on 400 CML-CP patients to look for the distribution of fusion transcripts i.e. b3a2 and b2a2, their clinico-hematological profile and impact on treatment response in patients treated with Imatinib.
Material and Methods: CML-CP was diagnosed by reverse transcriptase PCR (RT-PCR) for the BCR-ABL fusion transcript. Real-time quantitative PCR (RQ-PCR) was performed on peripheral blood every 3-6 monthly to look for treatment response.
Results: The overall frequency of b3a2 transcript was observed in 288 (72%) followed by b2a2 in 104 (26%) and hybrid fusion transcript (b3a2 + b2a2) was seen in 8 (2%) cases. MMR was attained in 198/288 (68.7%) patients with b3a2 transcript and 90/288 (31.3%) patients failed to achieve MMR after 12 months of Imatinib therapy. Among the patients with b2a2 transcript, 44/104 (42.3%) patients achieved MMR and 60/104 (57.7%) patients failed to achieve MMR after 12 months of Imatinib therapy.
Conclusions: In conclusion, the frequency of b3a2 transcript was more as compared to b2a2 transcript. MMR was significantly higher in patients with b3a2 transcript as compared to patients with b2a2.

Wang X, Yang J, Guo G, et al.
Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.
Mol Cancer. 2019; 18(1):84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Möbius S, Schenk T, Himsel D, et al.
Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry).
J Cancer Res Clin Oncol. 2019; 145(6):1645-1650 [PubMed] Related Publications
PURPOSE: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every 3 months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR
METHODS: Data were collected on the standardized assessment of molecular response in the context of real-life practice. BCR-ABL1 transcript levels after > 2 years of TKI therapy were evaluated for DMR by local laboratories as well as standardized EUTOS laboratories. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out.
RESULTS: Between 2014 and 2017, 3377 peripheral blood samples from 1117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of the patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n = 197 (6.51%); MMR, n = 496 (16.40%); MR
CONCLUSIONS: Multicenter DMR assessment is feasible in the context of real-life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

Hassan FM
OGG1 rs1052133 Polymorphism and Genetic Susceptibility to Chronic Myelogenous Leukaemia
Asian Pac J Cancer Prev. 2019; 20(3):925-928 [PubMed] Related Publications
Background: In some cancer cells, the OGG1 gene is somatically mutated and highly populated. This study was conducted to examine whether OGG1 rs1052133 polymorphism is associated with the genetic background of chronic myelogenous leukaemia (CML) in Sudan. Methods: A total of 332 CML patients and 70 healthy controls were included in this study. Overall, the genotypes (P=0.0000) and allele (C vs. G, P=0.0007) differed considerably in the frequencies of OGG1 rs1052133 polymorphism between CML patients and controls. Our study is the first to evaluate the association of polymorphism with CML risk with OGG1 rs1052133. Results: A statistically significant association was observed between the genotype distribution of OGG1 rs1052133 polymorphism and CML (P=0.0000) patients. A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls when compared OGG1 rs1052133 genotypes with CML stages. Results: Genotype and allele frequencies of OGG1 rs1052133 among CML patients. A statistically significant association was observed between the genotype distribution of the OGG1 rs1052133 polymorphism and CML patients (P=0.0000). A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls with stages of CML in OGG1 rs1052133 genotypes. Conclusion: The results suggest that single nucleotide polymorphism in the gene involved in the restoration of DNA base excision (OGG1 rs1052133) can play a key role in the risk of appearance of CML. To clarify the role of OGG1 in the genetic basis of CML, further case control with larger sample sizes and fine-mapping is required.

Grifoni FI, Sciumè M, Pravettoni V, et al.
A case report of systemic mastocytosis associated with multiple hematologic non-mast cell lineage diseases.
Hematol Oncol. 2019; 37(2):205-211 [PubMed] Related Publications
Systemic mastocytosis (SM) is a hematological malignancy characterized by extracutaneous infiltration by atypical mast cells. Together with indolent SM, aggressive SM, and mast cell leukemia, the World Health Organization (WHO) recognizes another major disease subgroup: SM with an associated hematological neoplasm, which is characterized by the presence of a concurrent neoplasm, more commonly, a chronic myelomonocytic leukemia. While KIT D816V is commonly regarded as the driver mutation, the clinical presentation of SM is extremely varied. Treatment of SM might not be simple, but now more specific therapies tailored toward prognostic subgroups of patients have been developed. Here, we report a detailed description of clinical management and biological features of a systemic mastocytocis case associated with multiple hematologic non-mast cell lineage diseases.

Dulucq S, Etienne G, Morisset S, et al.
Impact of second decline rate of BCR-ABL1 transcript on clinical outcome of chronic phase chronic myeloid leukemia patients on imatinib first-line.
Ann Hematol. 2019; 98(5):1159-1168 [PubMed] Related Publications
Early molecular response has been associated with clinical outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The BCR-ABL1 transcript rate decline from baseline to 3 months has been demonstrated to be more predictive than a single BCR-ABL1 level at 3 months (M3). However, it cannot be used routinely because ABL1, as an internal gene control, is not reliable for BCR-ABL1 quantification above 10%. This study aimed to compare clinical outcome and molecular response of chronic phase CML patients, depending on the percentage of BCR-ABL1 transcript decrease from month 3 to month 6 using ABL1 as an internal control gene. Two hundred sixteen chronic phase CML patients treated with imatinib 400 mg for whom M3 and month 6 molecular data were available were included in the study. Associations with event-free (EFS), failure-free (FFS), progression-free (PFS), and overall survivals (OS) molecular response 4 log and 4.5 log were assessed. The percentage of BCR-ABL1 decline from month 3 to month 6 was significantly linked to the EFS and the FFS (p < 0.001). A common cut-off of 67% of decline predicted the better risk of event. Patients with a decrease below 67% have worse EFS and FFS as compared to those having a higher decrease (p < 0.001). The impact was confirmed by multivariate analysis. Since the slope between diagnosis and 3 months cannot be reliable using ABL1 as an internal gene control, the second decline rate of BCR-ABL1 transcript between month 3 and month 6 could efficiently identify patients at higher risk of event.

Ferri C, Weich N, Gutiérrez L, et al.
Single nucleotide polymorphism in PTEN-Long gene: A risk factor in chronic myeloid leukemia.
Gene. 2019; 694:71-75 [PubMed] Related Publications
The BCR-ABL1 oncogene is associated with chronic myeloid leukemia (CML) pathogenesis, but the molecular mechanisms that initiate leukemogenesis are still unclear. Cancer pathogenesis has been associated with genetic alterations that may lead to inactivation of tumor suppressor genes. Phosphatase and tensin homolog (PTEN) is frequently deleted or inactivated in various tumors. A recently discovered variant of PTEN, PTEN-Long (PTEN-L), results from an alternative translation initiation site located upstream of the canonic AUG and generates a protein of 576 amino acids instead the expected protein of 403 amino acids. A 16 bp perfect palindromic motif centered on the PTEN-L CUG

Baccarani M, Castagnetti F, Gugliotta G, et al.
The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview.
Leukemia. 2019; 33(5):1173-1183 [PubMed] Related Publications
There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associated with gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Uzoma IC, Taiwo IA, Nna EO, et al.
Detection of
Niger J Clin Pract. 2019; 22(1):51-55 [PubMed] Related Publications
Background: The presence of BCR-ABL1 fusion gene resulting from a t(9; 22) reciprocal chromosome translocation is the molecular hallmark of chronic myeloid leukemia (CML). In the diagnosis and treatment of CML, peripheral blood or bone marrow samples are usually taken for analysis. However, both methods are invasive sample collection methods, thus a noninvasive saliva sample method for the detection of the fusion gene transcripts (BCR-ABL) was investigated in some Nigerians with CML.
Materials and Methods: Real-time (RT)-polymerase chain reaction (PCR) analysis was used to detect BCR-ABL1 fusion gene in the saliva and blood of 42 Nigerian CML patients. RNA was extracted using RNeasy kit and reverse transcribed by random hexamer priming using murine Moloney reverse transcriptase. BCR-ABL1 transcript types were first detected by multiplex PCR and then quantified by a duplex RT-PCR-TaqMan chemistry with MGB probe and Black Hole Quencher.
Results: Of the 42 subjects, transcript types were detected in 36 (85.7%) samples, e13a2 fusion transcript sub-type was detected in 9 (21.4%), whereas e14a2 subtype was found in 27 (67.3%); six (14.3%) of the samples did not reveal any of the fusion transcript subtypes. The median BCR-ABL1 messenger RNA values were 9.38 × 10
Conclusion: Saliva may offer an alternative easy-to-collect, readily available, and noninvasive sample for the diagnosis and treatment of CML.

Farawela HM, Zawam HM, Al-Wakeel HA, et al.
Expression pattern and prognostic implication of SALL4 gene in myeloid leukemias: a case-control study.
Scand J Clin Lab Invest. 2019 Feb - Apr; 79(1-2):65-70 [PubMed] Related Publications
SALL4 is a transcription factor that retains stem cells in an undifferentiated state and promotes its self-renewal. In addition, it is implicated in leukemogenesis via its effect on leukemic stem cells. This study aimed to characterize the expression pattern of SALL4 gene in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) at different progression phases of the leukemic process and to assess its prognostic significance. Real-time PCR was used in 106 patients: 54 AML patients; 43 de novo and 11 in complete remission (CR), 52 CML patients; 31 in chronic phase (CP), 11 in deep molecular response (MR

Shvachko LP, Zavelevich MP, Gluzman DF, et al.
Vitamin Е activates expression of С/EBP alpha transcription factor and G-CSF receptor in leukemic K562 cells.
Exp Oncol. 2018; 40(4):328-331 [PubMed] Related Publications
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of BCR-ABL fusion oncogene. Tyrosine kinase inhibitors are the current treatment of CML, but secondary mutations finally contribute to therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML is now in the spotlight. The progression of CML to blast crisis is correlated with down-modulation of C/EBP alpha. Therefore, C/EBP alpha may be considered as a putative target in differentiation therapies in myeloid leukemias. The aim of the study was to assess the potential of vitamin E as the possible inducer of C/EBP alpha expression in BCR-ABL-positive CML K562 cells.
MATERIALS AND METHODS: RNA extracted from K562 cells cultured with valproic acid or vitamin E was converted to cDNA, RT-PCR reactions were carried out using HotStarTaq DNA polymerase with primers for C/EBP alpha and granulocyte colony-stimulating factor receptor (G-CSFR).
RESULTS: We have not found detectable expression of C/EBP alpha in K562 cells. Upon 48-h culture with vitamin E at a dose of 100 µM, K562 cells expressed both C/EBP alpha and G-CSFR.
CONCLUSION: Vitamin E restored the expression of C/EBP alpha mRNA in chronic myelogenous leukemia K562 cells. In this setting, G-CSFR expression in vitamin E treated K562 cells seems to suggest the activation to granulocytic differentiation. It should be further elucidated whether such effects of vitamin E on C/EBP alpha transcription factor are direct or mediated indirectly due to antioxidant properties of vitamin E.

Stella S, Massimino M, Tirrò E, et al.
B-ALL Relapses After Autologous Stem Cell Transplantation Associated With a Shift from e1a2 to e14a2
Anticancer Res. 2019; 39(1):431-435 [PubMed] Related Publications
BACKGROUND/AIM: The Philadelphia chromosome is found in 30% of acute lymphoblastic leukemia (ALL) patients, a distinct ALL subgroup where the BCR-ABL fusion gene is associated with poor prognosis. Treatment with tyrosine kinase inhibitors (TKIs) often induces complete remission and these patients subsequently undergo an autologous stem cell transplantation (ASCT). However, 20% of subjects experience a relapse associated with the selection of point-mutations in the BCR-ABL kinase domain. We report the clinical evolution of a Philadelphia-positive ALL patient co-expressing the e1a2 and e14a2 BCR-ABL transcript at diagnosis.
MATERIALS AND METHODS: Multiplex reverse transcriptase (RT)-PCR was used to detect BCR-ABL transcripts and their levels were measured by quantitative Real Time PCR. Clonal sequencing and next-generation sequencing (NGS) were used to identify mutations.
RESULTS: Although the patient underwent ASCT following treatment with multiple TKIs, he relapsed twice. The first time he exhibited the e1a2 transcript and the second time he presented only the e14a2 variant. Mutation analysis, performed by clonal sequencing and NGS, detected two alterations after the first relapse and a single mutation at the time of the second relapse.
CONCLUSION: The observed shift from the e1a2 to the e14a2 variant and the selection of TKI-resistant clones heavily contributed to the fatal evolution of the disease.

BCR-ABL Translocation in Acute Lymphoblastic Leukaemia


See also: BCR.htm gene

Latest Publications

Conant JL, Czuchlewski DR
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies.
Int J Lab Hematol. 2019; 41 Suppl 1:126-130 [PubMed] Related Publications
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like ALL or Ph-like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B-ALL with t(9;22)(q34.1;q11.2) BCR-ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%-20% of pediatric cases and 20%-30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR-ABL1-like ALL, particularly in adults and pediatric patients with high-risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR-ABL1-like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.

Ayón-Pérez MF, Pimentel-Gutiérrez HJ, Durán-Avelar MJ, et al.
IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico.
Cytogenet Genome Res. 2019; 158(1):10-16 [PubMed] Related Publications
The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.

Wang X, Yang J, Guo G, et al.
Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.
Mol Cancer. 2019; 18(1):84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Khan M, Siddiqi R, Tran TH
Philadelphia chromosome-like acute lymphoblastic leukemia: A review of the genetic basis, clinical features, and therapeutic options.
Semin Hematol. 2018; 55(4):235-241 [PubMed] Related Publications
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high-risk subtype of B-lineage ALL (B-ALL), characterized by a gene expression profile similar to that of Philadelphia-positive (Ph+) ALL, but without the hallmark BCR-ABL1 oncoprotein. Ph-like ALL represents approximately 15% of childhood ALL and its frequency rises with age, peaking among adolescents, and young adults with B-ALL. This subtype is associated with adverse clinical features, persistence of minimal residual disease, and a poor prognosis despite modern chemotherapy regimens. While Ph-like ALL lacks the BCR-ABL1 fusion, it is characterized by a diverse spectrum of kinase fusions and cytokine receptor gene rearrangements that may be similarly amenable to molecularly targeted therapies. While survival rates for childhood ALL have drastically improved with intensive conventional chemotherapy, Ph-like ALL represents a novel paradigm of precision medicine in ALL. This review aims to provide a comprehensive review of the clinical picture and genetic basis of Ph-like ALL and to illustrate how these findings can translate into tailored targeted therapies with the hopes of improving the outcomes of Ph-like ALL patients.

Jabbour E, Short NJ, Ravandi F, et al.
Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study.
Lancet Haematol. 2018; 5(12):e618-e627 [PubMed] Related Publications
BACKGROUND: The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial.
METHODS: In our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients.
FINDINGS: 76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision.
INTERPRETATION: The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive  acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted.
FUNDING: Takeda Oncology.

Li JF, Dai YT, Lilljebjörn H, et al.
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A. 2018; 115(50):E11711-E11720 [PubMed] Free Access to Full Article Related Publications
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with

Roberts KG
Why and how to treat Ph-like ALL?
Best Pract Res Clin Haematol. 2018; 31(4):351-356 [PubMed] Related Publications
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), or BCR-ABL1-like ALL, is a high-risk subtype of B-cell precursor ALL characterized by a gene expression profile similar to Ph-positive ALL, a high frequency of IKZF1 alterations, and poor outcome. The prevalence of Ph-like ALL is common among all ages, ranging from 10% to 15% in children to over 25% in young adults. Patients with Ph-like ALL harbor a diverse range of genetic alterations that activate cytokine receptor and kinase signaling and can be targeted with tyrosine kinase inhibitors. The majority of Ph-like ALL alterations are divided into two main groups based on activation of ABL-class or JAK-STAT alterations. Accordingly, preclinical studies and anecdotal reports suggest patients harboring ABL-class fusions are candidates for ABL1-inhibitors, whilst alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. Diagnostic screening approaches and precision medicine trials are now being developed and implemented to test the efficacy of targeted therapy with a backbone of chemotherapy, similar to the treatment of Ph-positive ALL.

Rothfelder K, Hagelstein I, Roerden M, et al.
Expression of the Immune Checkpoint Modulator OX40 in Acute Lymphoblastic Leukemia Is Associated with BCR-ABL Positivity.
Neoplasia. 2018; 20(11):1150-1160 [PubMed] Free Access to Full Article Related Publications
OX40 and its ligand are members of the TNF/TNF receptor superfamily, which includes various molecules influencing cellular signaling and function of both tumor and immune cells. The ability of OX40 to promote proliferation and differentiation of activated T cells fueled present attempts to modulate this immune checkpoint to reinforce antitumor immunity. While we recently found evidence for the involvement of OX40 in pathophysiology of acute myeloid leukemia including natural killer (NK) cell immunosurveillance, less is known on its role in acute lymphoblastic leukemia (ALL). In the present study, OX40 expression on ALL cells was significantly associated with positivity for the adverse risk factor BCR-ABL. In line, signaling via OX40 increased metabolic activity of primary ALL cells and resulted in release of cytokines involved in disease pathophysiology. Furthermore, interaction of ALL-expressed OX40 with its cognate ligand on NK cells stimulated ALL cell lysis. The data presented thus not only identify the yet unknown involvement of OX40/OX40L in ALL pathophysiology and NK cell immunosurveillance but also point to the necessity to thoroughly consider the consequences of modulating the OX40/OX40L molecule system beyond its effects on T cells when developing OX40-targeting approaches for cancer immunotherapy.

Parihar M, Singh MK, Islam R, et al.
A triple-probe FISH screening strategy for risk-stratified therapy of acute lymphoblastic leukaemia in low-resource settings.
Pediatr Blood Cancer. 2018; 65(12):e27366 [PubMed] Free Access to Full Article Related Publications
Karyotyping along with a 3-probe fluorescence in situ hybridization (FISH) strategy was used to risk stratify therapy in 303 children with B-cell precursor acute lymphoblastic leukaemia. Of the 166 patients risk stratified, karyotype identified 91 (55%). FISH identified all karyotypes accurately, with the exception of hypodiploidy, and risk stratified an additional 75 patients. The frequency of ETV6-RUNX1 is lower and high hyperdiploidy, higher than reported in the west. An adapted 3-probe FISH strategy identified two patients with ETV6-ABL1 fusion who received imatinib. In limited-resource settings, a 3-probe FISH approach provides a practical approach for risk-stratified therapy in childhood ALL.

Chen X, Wang F, Zhang Y, et al.
Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia.
Leuk Res. 2018; 72:99-104 [PubMed] Related Publications
Fusion genes are major molecular biological abnormalities in hematological malignancies. To depict the common recurrent gene-fusion landscape in acute lymphoblastic leukemia (ALL), 36 recurrent fusion genes in hematologic malignancies were assessed using multiplex-nested RT-PCR in 2479 patients with de novo ALL. 17 kinds of distinct fusion genes were detected in 712 (28.72%) cases. Co-occurrence of different fusion genes was observed in 6 (0.24%) patients. Incidence of fusion genes in B-ALL was significantly higher than in T-ALL (31.40% vs. 14.50%, P < 0.001). Pediatric ALL had higher prevalence of ETV6-RUNX1, TCF3-PBX1, and STIL-TAL1, while BCR-ABL1 and SET-NUP214 were more common in adult ALL. BCR-ABL1, TCF3-PBX1, KMT2A-AFF1 and ETV6-RUNX1 were more frequent in B-ALL. On the contrary, KMT2A-MLLT4, SET-NUP214 and STIL-TAL1 were of higher incidence in T-ALL. In comparison with Western cohorts, the incidence of BCR-ABL1 (5.94%) was much higher in our series, while the occurrence of ETV6-RUNX1 (13.19%) was significantly lower in pediatric B-ALL patients in our study than in Western reports. This study provides a genetic landscape of common fusion genes in ALL patients and may serve as a foundation for further improvement of a fusion gene screening panel for clinical applications.

Vanden Bempt M, Demeyer S, Broux M, et al.
Cooperative Enhancer Activation by TLX1 and STAT5 Drives Development of NUP214-ABL1/TLX1-Positive T Cell Acute Lymphoblastic Leukemia.
Cancer Cell. 2018; 34(2):271-285.e7 [PubMed] Free Access to Full Article Related Publications
The NUP214-ABL1 fusion is a constitutively activated tyrosine kinase that is significantly associated with overexpression of the TLX1 and TLX3 transcription factors in T cell acute lymphoblastic leukemia (T-ALL). Here we show that NUP214-ABL1 cooperates with TLX1 in driving T-ALL development using a transgenic mouse model and human T-ALL cells. Using integrated ChIP-sequencing, ATAC-sequencing, and RNA-sequencing data, we demonstrate that TLX1 and STAT5, the downstream effector of NUP214-ABL1, co-bind poised enhancer regions, and cooperatively activate the expression of key proto-oncogenes such as MYC and BCL2. Inhibition of STAT5, downregulation of TLX1 or MYC, or interference with enhancer function through BET-inhibitor treatment leads to reduction of target gene expression and induction of leukemia cell death.

Roberts KG, Reshmi SC, Harvey RC, et al.
Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.
Blood. 2018; 132(8):815-824 [PubMed] Free Access to Full Article Related Publications
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL;

Wenzinger C, Williams E, Gru AA
Updates in the Pathology of Precursor Lymphoid Neoplasms in the Revised Fourth Edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues.
Curr Hematol Malig Rep. 2018; 13(4):275-288 [PubMed] Related Publications
PURPOSE OF REVIEW: Acute lymphoblastic leukemias (ALL) are malignant disorders of immature B or T cells that occur characteristically in children, usually under the age of 6 (75%). Approximately 6000 new cases of ALL are diagnosed each year in the USA, 80-85% of which represent B-ALL forms. Most presentations of B-ALL are leukemic, whereas T-ALL presents with a mediastinal mass, with or without leukemic involvement. The revised fourth edition of the World Health Organization (WHO) classification (2017) has introduced some changes in both B and T-ALL. Here, we summarize the categories of lymphoblastic leukemia/lymphomas as defined by the WHO and recent developments in the understanding of this group of hematologic malignancy.
RECENT FINDINGS: Two provisional categories of B-ALL have now been identified including B-ALL, BCR-ABL1-like, and B-ALL with iAMP21. The Philadelphia chromosome-like B-ALL includes forms of the disease that shares the expression profiling of B-ALL with t(9;22) but lack such rearrangement. The second one shows amplification of part of the chromosome 21. Both entities are associated with worse prognosis. Within the T-ALL group, an early precursor T cell form has now been introduced as a provisional category. Such group demonstrates expression of stem cell and myeloid markers in conjunction with the T cell antigens. The current review summarizes the recent updates to the WHO classification.

Short NJ, Kantarjian H, Pui CH, et al.
SOHO State of the Art Update and Next Questions: Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
Clin Lymphoma Myeloma Leuk. 2018; 18(7):439-446 [PubMed] Related Publications
The widespread adoption of Bcr-Abl-directed tyrosine kinase inhibitors (TKIs) into first-line regimens for patients with Philadelphia chromosome (Ph)-positive (Ph

Greaves M
A causal mechanism for childhood acute lymphoblastic leukaemia.
Nat Rev Cancer. 2018; 18(8):471-484 [PubMed] Related Publications
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1)

Lukes J, Potuckova E, Sramkova L, et al.
Two novel fusion genes, AIF1L-ETV6 and ABL1-AIF1L, result together with ETV6-ABL1 from a single chromosomal rearrangement in acute lymphoblastic leukemia with prenatal origin.
Genes Chromosomes Cancer. 2018; 57(9):471-477 [PubMed] Related Publications
Fusion genes resulting from chromosomal rearrangements represent a hallmark of childhood acute lymphoblastic leukemia (ALL). Unlike more common fusion genes generated via simple reciprocal chromosomal translocations, formation of the ETV6-ABL1 fusion gene requires 3 DNA breaks and usually results from an interchromosomal insertion. We report a child with ALL in which a single interchromosomal insertion led to the formation of ETV6-ABL1 and 2 novel fusion genes: AIF1L-ETV6 and ABL1-AIF1L. We demonstrate the prenatal origin of this complex chromosomal rearrangement, which apparently initiated the leukemogenic process, by successful backtracking of the ETV6-ABL1 fusion into the patient's archived neonatal blood. We cloned coding sequences of AIF1L-ETV6 and ABL1-AIF1L in-frame fusion transcripts from the patient's leukemic blasts and we show that the chimeric protein containing the DNA binding domain of ETV6 is expressed from the AIF1L-ETV6 transcript and localized in both the cytoplasm and nucleus of transfected HEK293T cells. Transcriptomic and genomic profiling of the diagnostic bone marrow sample revealed Ph-like gene expression signature and loss of the IKZF1 and CDKN2A/B genes, the typical genetic lesions accompanying ETV6-ABL1-positive ALL. The prenatal origin of the rearrangement confirms that ETV6-ABL1 is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions. We did not find the AIF1L-ETV6 and ABL1-AIF1L fusions in other ETV6-ABL1-positive ALL. Nevertheless, functional studies would be needed to establish the biological role of AIF1L-ETV6 and ABL1-AIF1L and to determine whether they contribute to leukemogenesis and/or to the final leukemia phenotype.

Chiaretti S, Messina M, Grammatico S, et al.
Rapid identification of BCR/ABL1-like acute lymphoblastic leukaemia patients using a predictive statistical model based on quantitative real time-polymerase chain reaction: clinical, prognostic and therapeutic implications.
Br J Haematol. 2018; 181(5):642-652 [PubMed] Free Access to Full Article Related Publications
BCR/ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B-lineage acute lymphoblastic leukaemia that occurs within cases without recurrent molecular rearrangements. Gene expression profiling (GEP) can identify these cases but it is expensive and not widely available. Using GEP, we identified 10 genes specifically overexpressed by BCR/ABL1-like ALL cases and used their expression values - assessed by quantitative real time-polymerase chain reaction (Q-RT-PCR) in 26 BCR/ABL1-like and 26 non-BCR/ABL1-like cases to build a statistical "BCR/ABL1-like predictor", for the identification of BCR/ABL1-like cases. By screening 142 B-lineage ALL patients with the "BCR/ABL1-like predictor", we identified 28/142 BCR/ABL1-like patients (19·7%). Overall, BCR/ABL1-like cases were enriched in JAK/STAT mutations (P < 0·001), IKZF1 deletions (P < 0·001) and rearrangements involving cytokine receptors and tyrosine kinases (P = 0·001), thus corroborating the validity of the prediction. Clinically, the BCR/ABL1-like cases identified by the BCR/ABL1-like predictor achieved a lower rate of complete remission (P = 0·014) and a worse event-free survival (P = 0·0009) compared to non-BCR/ABL1-like ALL. Consistently, primary cells from BCR/ABL1-like cases responded in vitro to ponatinib. We propose a simple tool based on Q-RT-PCR and a statistical model that is capable of easily, quickly and reliably identifying BCR/ABL1-like ALL cases at diagnosis.

Aoe M, Ishida H, Matsubara T, et al.
Simultaneous detection of ABL1 mutation and IKZF1 deletion in Philadelphia chromosome-positive acute lymphoblastic leukemia using a customized target enrichment system panel.
Int J Lab Hematol. 2018; 40(4):427-436 [PubMed] Related Publications
INTRODUCTION: Recent clinical outcomes of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary.
METHODS: We evaluated a next-generation sequencing (NGS)-based customized HaloPlex target enrichment system panel to simultaneously detect coding mutations, indel and CNVs. We analysed approximately 160 known genes associated with hematological disorders in 5 pediatric Ph+ALL patients.
RESULTS: Mono-allelic IKZF1 deletions were found in 4 patients at diagnosis. Furthermore, the mono-allelic deletions were found in exons of RB1, EBF1, PAX5 and ETV6 genes. Bi-allelic deletions were detected in CDKN2A and CDKN2B genes in 1 patient. ABL1 mutation was also detected in 1 patient at relapse. These results were almost comparable with the results of the multiplex ligation-dependent probe amplification (MLPA) method or Sanger sequence.
CONCLUSION: Next-generation sequencing-based custom HaloPlex target enrichment system panel allows us to detect the coding mutations, indel, and CNVs in pediatric Ph+ALL simultaneously, and its results seem comparable with those of other methods.

McClure BJ, Heatley SL, Kok CH, et al.
Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression.
Br J Cancer. 2018; 118(7):1000-1004 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Zinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome.
METHODS: Bone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes.
RESULTS: We exclusively detect E1A-associated protein p300 (EP300)-ZNF384 in 5.7% of BCR-ABL1-negative adolescent/young adult (AYA)/adult pre-B-ALL patients. EP300-ZNF384 patients do not appear to be a high-risk subgroup. Transcriptomic analysis revealed that EP300-ZNF384 samples have a distinct gene expression profile that results in the up-regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and cell adhesion pathways and down-regulation of cell cycle and DNA repair pathways.
CONCLUSIONS: Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity.

Tran TH, Harris MH, Nguyen JV, et al.
Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia.
Blood Adv. 2018; 2(5):529-533 [PubMed] Free Access to Full Article Related Publications
Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (

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