Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
RUNX1 is implicated in: - ATP binding
- basement membrane
- behavioral response to pain
- calcium ion binding
- central nervous system development
- definitive hemopoiesis
- DNA binding
- embryonic hemopoiesis
- hair follicle morphogenesis
- hematopoietic stem cell proliferation
- in utero embryonic development
- intracellular membrane-bounded organelle
- liver development
- myeloid cell differentiation
- myeloid progenitor cell differentiation
- negative regulation of granulocyte differentiation
- peripheral nervous system neuron development
- positive regulation of angiogenesis
- positive regulation of granulocyte differentiation
- positive regulation of transcription from RNA polymerase II promoter
- positive regulation of transcription, DNA-dependent
- protein binding
- protein heterodimerization activity
- protein homodimerization activity
- regulation of hair follicle cell proliferation
- regulation of signal transduction
- regulatory region DNA binding
- repressing transcription factor binding
- sequence-specific DNA binding transcription factor activity
- skeletal system development
- transcription factor binding
- transcription, DNA-dependent
Data from Gene Ontology via CGAP [Hide]
t(8;21)(q22;q22) in Acute Myeloid Leukemia The t(8;21) translocation is the most frequent cytogenetic abnormality in acute myeloid leukaemia (AML). The translocation fuses the RUNX1 (CBFA2, AML1) gene on chromosome 21q to the RUNX1T1 (CBFA2T1, ETO) gene on chromosome 8q. The resulting fusion gene AML1-ETO occurs more frequently, though not exclusively, in the AML-M2 sub-type. In a series of 64 AML cases Andrieu et al (1996) detected the fusion in 3% (1/32) of M1 patients compared to 8/32 (25%) with M2. It is detected in approximately 20% of adult and 40% of paediatric patients with AML-M2.
Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.
Translation and transcription are frequently dysregulated in cancer. These two processes are generally regulated by distinct sets of factors. The CBFB gene, which encodes a transcription factor, has recently emerged as a highly mutated driver in a variety of human cancers including breast cancer. Here we report a noncanonical role of CBFB in translation regulation. RNA immunoprecipitation followed by deep sequencing (RIP-seq) reveals that cytoplasmic CBFB binds to hundreds of transcripts and regulates their translation. CBFB binds to mRNAs via hnRNPK and enhances translation through eIF4B, a general translation initiation factor. Interestingly, the RUNX1 mRNA, which encodes the transcriptional partner of CBFB, is bound and translationally regulated by CBFB. Furthermore, nuclear CBFB/RUNX1 complex transcriptionally represses the oncogenic NOTCH signaling pathway in breast cancer. Thus, our data reveal an unexpected function of CBFB in translation regulation and propose that breast cancer cells evade translation and transcription surveillance simultaneously through downregulating CBFB.
Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.
Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10-25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. Here we report that EVI1 upregulation is associated with methylation of the miR-9 promoter and correlated with downregulation of miR-9 in human AML cell lines and bone marrow (BM) cells from pediatric patients. Reactivation of miR-9 by hypomethylating agents and forced expression of miR-9 in EVI1
Shin HJ, Min WS, Min YH, et al. Different prognostic effects of core-binding factor positive AML with Korean AML registry data. Ann Hematol. 2019; 98(5):1135-1147 [PubMed] Related Publications
Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.
Piskunova IS, Obukhova TN, Parovichnikova EN, et al. Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia. Ter Arkh. 2018; 90(7):30-37 [PubMed] Related Publications
AIM: To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. MATERIALS AND METHODS: The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification. RESULTS: Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p<0.0001) and chance of recurrence (HR - 6.4; p=0.02). CONCLUSION: Adverse prognostic factors in terms of therapeutic management provided in ALL-2009 protocol were MLL/t(11q23) and с-MYC/t(8q24) genes abnormalities. CDKN2A/9p21 and TP53/17p13 genes deletions, quantative and complex karyotype abnormalities were not prognostic factors in adult patients with Ph-negative ALL in ALL-2009 protocol use.
Wang X, Jiang X, Zhou L, et al. LncRNA‑NEF is involved the regulation of gastric carcinoma cell proliferation by targeting RUNX1. Mol Med Rep. 2019; 19(3):2051-2056 [PubMed] Related Publications
Neighboring enhancer of FOXA2 (NEF) is a newly discovered long non‑coding RNA (lncRNA) that serves an oncogenic function in the metastasis of hepatocellular carcinoma, while its involvement in other types of cancer and in tumor cell proliferation remain unknown. In the present study, tumor tissues and adjacent healthy tissues were obtained from patients with gastric carcinoma, and blood was extracted from patients with gastric carcinoma and healthy controls. Expression of NEF in those tissues was detected using a reverse transcription‑quantitative polymerase chain reaction. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic value of serum lncRNA NEF for gastric carcinoma. All patients were followed‑up for 5 years following discharge, and survival curves were plotted to evaluate the diagnostic value of serum lncRNA‑NEF for gastric carcinoma. LncRNA‑NEF overexpression and small interfering RNA (siRNA) silencing cell lines were established and the effects on cell proliferation and runt‑related transcription factor 1 (Runx1) expression were detected using a Cell Counting Kit‑8 assay and western blot analysis, respectively. It was revealed that NEF was significantly downregulated in tumor tissues compared with in adjacent tissues. Levels of circulation NEF in serum were lower in patients with gastric carcinoma compared with in healthy controls, and were decreased with the increasing stages of primary tumor. Serum NEF is a sensitive diagnostic and prognostic marker for gastric carcinoma. NEF siRNA silencing promoted, and overexpression inhibited, gastric carcinoma proliferation. In addition, NEF overexpression promoted, and NEF siRNA silencing inhibited, Runx1 expression. Therefore, it was concluded that lncRNA NEF may participate in the regulation of cancer cell proliferation by regulating Runx1 expression.
BACKGROUND: Changes in glycosylation are known to play critical roles during gastric carcinogenesis. Expression of truncated O-glycans, such as the Sialyl-Tn (STn) antigen, is a common feature shared by many cancers and is associated with cancer aggressiveness and poor-prognosis. METHODS: Glycoengineered cell lines were used to evaluate the impact of truncated O-glycans in cancer cell biology using in vitro functional assays, transcriptomic analysis and in vivo models. Tumor patients 'samples and datasets were used for clinical translational significance evaluation. FINDINGS: In the present study, we demonstrated that gastric cancer cells expressing truncated O-glycans display major phenotypic alterations associated with higher cell motility and cell invasion. Noteworthy, the glycoengineered cancer cells overexpressing STn resulted in tumor xenografts with less cohesive features which had a critical impact on mice survival. Furthermore, truncation of O-glycans induced activation of EGFR and ErbB2 receptors and a transcriptomic signature switch of gastric cancer cells. The disclosed top activated genes were further validated in gastric tumors, revealing that SRPX2 and RUNX1 are concomitantly overexpressed in gastric carcinomas and its expression is associated with patients' poor-survival, highlighting their prognosis potential in clinical practice. INTERPRETATION: This study discloses novel molecular links between O-glycans truncation frequently observed in cancer and key cellular regulators with major impact in tumor progression and patients' clinical outcome.
Oncogenic fusion protein RUNX1-ETO is the product of the t(8;21) translocation, responsible for the most common cytogenetic subtype of acute myeloid leukemia. RUNX1, a critical transcription factor in hematopoietic development, is fused with almost the entire ETO sequence with the ability to recruit a wide range of repressors. Past efforts in providing a comprehensive picture of the genome-wide localization and the target genes of RUNX1-ETO have been inconclusive in understanding the underlying mechanism by which it deregulates native RUNX1. In this review; we dissect the current data on the epigenetic impact of RUNX1 and RUNX1-ETO. Both share similarities however, in recent years, research focused on epigenetic factors to explain their differences. RUNX1-ETO impairs DNA repair mechanisms which compromises genomic stability and favors a mutator phenotype. Among an increasing pool of mutated factors, regulators of DNA methylation are frequently found in t(8;21) AML. Together with the alteration of both, histone markers and distal enhancer regulation, RUNX1-ETO might specifically disrupt normal chromatin structure. Epigenetic studies on the fusion protein uncovered new mechanisms contributing to leukemogenesis and hopefully will translate into clinical applications.
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene,
Bashanfer SAA, Saleem M, Heidenreich O, et al. Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1‑RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells. Oncol Rep. 2019; 41(3):2027-2040 [PubMed] Related Publications
The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.
Debaize L, Jakobczyk H, Avner S, et al. Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation. Nucleic Acids Res. 2018; 46(21):11214-11228 [PubMed] Free Access to Full ArticleRelated Publications
Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.
Shi J, Zhong X, Song Y, et al. Long non-coding RNA RUNX1-IT1 plays a tumour-suppressive role in colorectal cancer by inhibiting cell proliferation and migration. Cell Biochem Funct. 2019; 37(1):11-20 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the progression of various cancers. In this study, we aim to investigate the role of lncRNA RUNX1-IT1 in the development of colorectal cancer (CRC). The expression levels of lncRNA RUNX1-IT1 were measured using quantitative real-time Polymerase Chain Reaction(qRT-PCR). CCK8 proliferation assay, transwell assay, and flow cytometry were performed to evaluate the effect of lncRNA RUNX1-IT1 on CRC cell proliferation, migration, and apoptosis. The proliferation markers (PCNA, Ki67), apoptosis markers (cleaved-PARP, cleaved-caspase3), and MMP9 are detected by western blotting. Significant down regulation of lncRNA RUNX1-IT1 was measured in CRC tissues and three CRC cell lines (HCT116, HT29, and RKO) compared with paired nontumorous adjacent tissues (P < 0.01) or the normal colonic epithelial cell line FHC (P < 0.05), respectively. Moreover, the proliferative and migration potential of CRC cells were inhibited by overexpressing lncRNA RUNX1-IT1, which could be obviously improved by knocking down lncRNA RUNX1-IT1. The protein levels of PCNA, Ki67, and MMP9 were upregulated by overexpressing lncRNA RUNX1-IT1 and down regulated in si-RUNX1-IT1 cells. Besides, lncRNA RUNX1-IT1 could also promote the apoptosis of CRC cells. In conclusion, lncRNA RUNX1-IT1 is downregulated in CRC and plays a tumour-suppressive role due to the regulatory of cell proliferation, migration, and apoptosis. SIGNIFICANCE OF THE STUDY: We demonstrated that lncRNA RUNX1-IT1 was down regulated both in CRC tissues and cell lines. Besides, lncRNA RUNX1-IT1 could serve as a potential diagnostic biomarker and play a tumour-suppressive role owing to its good diagnostic efficacy and inhibition of CRC cell proliferation and migration.
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 ArticleRelated 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
Singh M, Bhatia P, Shandilya JK, et al. Low Expression of Leucocyte Associated Immunoglobulin Like Receptor-1 (LAIR-1/CD305) in a Cohort of Pediatric Acute Lymphoblastic Leukemia Cases Asian Pac J Cancer Prev. 2018; 19(11):3131-3135 [PubMed] Free Access to Full ArticleRelated Publications
Background: Immunophenotypic markers can play significant role in prognostic assessment for different cancers
and leukocyte-associated Ig-like receptor (LAIR-1) is a recently identified inhibitory immuno-receptor. Methods: We
measured LAIR-1 expression in paediatric ALL patients (n-42) and appropriate controls by flow cytometry. Median
fluorescence intensities (MFIs) were calculated and correlated with demographic and clinical variables and early
treatment outcome parameters. Results: The ALL cohort had an age range of 1 - 11 y and a M:F ratio of 2.5:1. 64%
had WBC counts <50 x 109/L and 15 (36%) >50 x 109/L, 52% being standard risk and 48% high risk. There were 6
cases of T-ALL and 36 of B-ALL. AML1-TEL, E2A-PBX, BCR-ABL and MLL-AF4 transcripts were noted in 3, 6,
2 and 1 patient, respectively. Day 8 ABC was <1,000 in 31 and >1,000 in 8 cases, while 30 had low and 7 high MRD
(both >0.01) at day 35 of treatment. The median MFI for LAIR-1 expression in control cases was 8.2 (range 7.76-11.69)
and in ALL cases 4.02 (range 0.56 to 11.87), with 74% (n-31) of ALL cases showing reduced LAIR-1 expression.
However, no significant correlations were found between standard ALL risk factors and LAIR-1 expression. Out of
42 patients, 4 died during induction treatment and one exited therapy, 60% (n-3/5) of these featuring low expression
of LAIR-1. Also ALL patients with low LAIR-1 expression had t (12;21), t (1;19) and t (4;11) translocations in 2, 4
and 1 samples, respectively, but none had t (9;22). Of those with high LAIR-1 expression, 2 had t (9;22) (MFIs-14.43
and 11.87). Conclusions: This pilot study of LAIR-1expression in ALL suggests low expression of the inhibitory
molecule in leukemic cells. However, the findings need to be confirmed with larger cohort, along with studies focusing
on pathophysiological roles in leukemic clone survival and escape from the immune system.
Naarmann-de Vries IS, Sackmann Y, Klein F, et al. Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region. Leuk Res. 2019; 76:15-23 [PubMed] Related Publications
Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q).
Obrochta E, Godley LA Identifying patients with genetic predisposition to acute myeloid leukemia. Best Pract Res Clin Haematol. 2018; 31(4):373-378 [PubMed] Related Publications
Germline syndromes in myeloid leukemias are being discovered increasingly in patients, and their identification is essential for proper medical management to yield positive health outcomes for patients and their families. There needs to be a greater appreciation of germline predisposition driving the development of hematologic malignancies within the field of myeloid malignancies. Characterization of the influence of germline mutations on the development of myeloid malignancies is ongoing by utilization of next generation sequencing data and prognostic panels. Here, we propose modifications to the utilization and analysis of genetic results, specifically to have a high index of clinical suspicion for germline predisposition, to use assays that are comprehensive for detection of these variants, and a few caveats to interpreting sequencing data. Presented are the benefits and shortcomings of prognostic panels and clinical examples of the utilization of the prognostic panel used within the Department of Pathology at The University of Chicago. The examples demonstrate that panels performed for prognostication on DNA derived from malignant cells are able to identify patients with germline syndromes, but they can lack coverage for genes that confer inherited susceptibility. Furthermore, the panels are often not designed to find duplication and deletion mutations, which calls for a need to improve assay design and bioinformatic approaches to interpret such variants using these data.
Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018; 19(12):1668-1679 [PubMed] Related Publications
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis p INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
Zámečníkova A, Al Bahar S A Novel and Cytogenetically Cryptic t(7;21)(q36.1;q22) Disrupting RUNX1 in Acute Myeloid Leukemia. Cytogenet Genome Res. 2018; 156(3):140-143 [PubMed] Related Publications
Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report here a novel RUNX1 partner gene, KMT2C (MLL3), in a patient with de novo acute myeloid leukemia, having a novel and cytogenetically cryptic t(7;21)(q36.1;q22) leading to disruption of RUNX1 and KMT2C. This is the third cryptic RUNX1 rearrangement in myeloid and the fourth in hematologic malignancies.
Celik H, Koh WK, Kramer AC, et al. JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells. Cancer Cell. 2018; 34(5):741-756.e8 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either reduced overall survival of animals with MPNs or drove transformation to sAML, depending on the timing and context of co-operating mutations. Mechanistically, JARID2 recruits PRC2 to epigenetically repress self-renewal pathways in hematopoietic progenitor cells. These studies establish JARID2 as a bona fide hematopoietic tumor suppressor and highlight potential therapeutic targets.
Assi SA, Imperato MR, Coleman DJL, et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet. 2019; 51(1):151-162 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.
Gao L, Tober J, Gao P, et al. RUNX1 and the endothelial origin of blood. Exp Hematol. 2018; 68:2-9 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The transcription factor RUNX1 is required in the embryo for formation of the adult hematopoietic system. Here, we describe the seminal findings that led to the discovery of RUNX1 and of its critical role in blood cell formation in the embryo from hemogenic endothelium (HE). We also present RNA-sequencing data demonstrating that HE cells in different anatomic sites, which produce hematopoietic progenitors with dissimilar differentiation potentials, are molecularly distinct. Hemogenic and non-HE cells in the yolk sac are more closely related to each other than either is to hemogenic or non-HE cells in the major arteries. Therefore, a major driver of the different lineage potentials of the committed erythro-myeloid progenitors that emerge in the yolk sac versus hematopoietic stem cells that originate in the major arteries is likely to be the distinct molecular properties of the HE cells from which they are derived. We used bioinformatics analyses to predict signaling pathways active in arterial HE, which include the functionally validated pathways Notch, Wnt, and Hedgehog. We also used a novel bioinformatics approach to assemble transcriptional regulatory networks and predict transcription factors that may be specifically involved in hematopoietic cell formation from arterial HE, which is the origin of the adult hematopoietic system.
Wu Y, Xu J, Shen K, et al. Acute myeloid leukemia with new complex t(8;21;22) induced hemophagocytic lymphohistiocytosis: A case report. Medicine (Baltimore). 2018; 97(44):e12762 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
RATIONALE: The balanced translocation t(8;21;22)(q22;q22;q11.2) is not reported previously, although t(8;21)(q22;q22) is seen in approximately 7% of adults and most frequent abnormality in children with newly diagnosed acute myeloid leukemia (AML). AML-associated hemophagocytic lymphohistiocytosis (HLH) is a rare event, reported only of limited numbers. The present study reports a very rare case of t(8;21;22)(q22;q22;q11.2) with AML, not reported previously, and developed HLH at the same time. PATIENT CONCERNS AND DIAGNOSIS: A 15-year-old girl presented with a history of bleeding gums and high fever, leukocytosis, anemia, and thrombocytopenia. While waiting the result of bone marrow aspirate, the HLH-associated examinations were abnormal. Bone marrow aspirate showed a hypercellular marrow with 1% myeloblasts. The cytogenetic and molecular studies revealed the presence of abnormal karyotype-46, XX, t(8;21;22)(q22;q22;q11.2) and RUNX1-RUNX1T1 fusion gene. Genetic detections of HLH showed heterozygous genetic variants in lysosomal trafficking regulator (LYST). Hence, she was diagnosed with AML with t(8;21;22)(q22;q22;q11.2) and HLH. INTERVENTIONS AND OUTCOMES: All HLH clinical symptoms disappeared after the 4 weeks treatment of HLH. Then the patient received standard AML induction chemotherapy and the leukemia relapsed after 2 cycles of high-dosed consolidation therapy. Eventually, the patient received emergent paternal haploidentical hematopoietic stem cell transplantation based on the complex variant translocation, leukemia replased state and HLH with compound heterozygotes mutation, and achieved sustained remission with RUNX1-RUNX1T1 negative for more than 1 year. LESSONS: Patients with some specific recurrent cytogenetic abnormalities should be diagnosed with AML regardless of the blast count, for example t(8;21). We should improve the understanding of complex variant translocations. HLH-related genetic mutations were not only found in primary HLH, but also in second HLH.
Benhassine M, Guérin SL Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma. Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the
Tyner JW, Tognon CE, Bottomly D, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018; 562(7728):526-531 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
Fei DL, Zhen T, Durham B, et al. Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene Proc Natl Acad Sci U S A. 2018; 115(44):E10437-E10446 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of
Kobayashi H, Satake N, Kaneko Y Detection of the Der (21)t(12;21) chromosome forming the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia. Leuk Lymphoma. 1997; 28(1-2):43-50 [PubMed] Related Publications
The t(12;21) (p13;q22) is observed in approximately 20-25% of childhood B-lineage acute lymphoblastic leukemia (ALL) cases in both Asian and Caucasian populations. This translocation results in the fusion of TEL, a recently described ETS-like gene on 12p13, and AML1, which was shown to be involved in the formation of fusion genes with ETO and EVI1 in myeloid leukemias. Fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis are useful in detecting this translocation which is not readily identified with routine cytogenetic techniques. The t(12;21) is associated with a distinct subgroup of patients characterized by an age between 1 and 10 years, an early B immunophenotype, and a good prognosis. A high incidence of the deletion of non-translocated TEL is another characteristic of leukemic cells with this translocation. TEL-AML1 hybrid protein thought to be critical in leukemogenesis possesses the HLH domain of TEL fused to almost the entire AML1 protein, although the detailed mechanisms of leukemogenesis remain obscure. RT-PCR combined with FISH analysis of posttreatment samples appears to be useful in detecting early relapse or minimal residual disease and thus, is expected to optimize the treatment strategy for patients with t(12;21).
Aguiar RC, Sohal J, van Rhee F, et al. TEL-AML1 fusion in acute lymphoblastic leukaemia of adults. M.R.C. Adult Leukaemia Working Party. Br J Haematol. 1996; 95(4):673-7 [PubMed] Related Publications
A number of fusion genes have been identified by study of acquired chromosomal translocations. Their detailed characterization has provided insights into mechanisms of leukaemogenesis and has enabled the development of molecular methods to assist in the diagnosis and monitoring of residual disease after treatment. The TEL-AML1 fusion gene is associated with a cryptic t(12:21)(p12:q22) translocation, and is the commonest known genetic abnormality in childhood B-cell precursor acute lymphoblastic leukaemia (ALL), occurring in about 25% of cases. We have used RT-PCR, followed by Southern blotting and direct sequencing, to establish the incidence of TEL-AML1 rearrangement in 131 adults with acute leukaemia (101 with ALL and 30 with chronic myeloid leukaemia in blastic crisis). Three patients were positive for TEL-AML1 transcripts. All three had common-ALL. All other patients were negative for TEL-AML1. We conclude that the TEL-AML1 fusion gene is found in adult ALL, though less commonly than in children.
Kwong YL, Wong KF Low frequency of TEL/AML1 in adult acute lymphoblastic leukemia. Cancer Genet Cytogenet. 1997; 98(2):137-8 [PubMed] Related Publications
Translocation (12;21)(p13;q22) is a recently characterized aberration in acute lymphoblastic leukemia, and results in the fusion of the TEL and the AML1 genes. It is the most common translocation in pediatric acute lymphoblastic leukemia (ALL), occurring in about one third of the cases. To determine the frequency of TEL/AML1 in adult ALL, we studied 4 cases of T lineage ALL and 26 cases of B lineage ALL. Only one positive case was identified, giving a very low frequency of 3.3%. In this patient, TEL/AML1 was still detectable in complete hematologic remission. The apparent age predilection of t(12;21) warrants further investigations.
Andrieu V, Radford-Weiss I, Troussard X, et al. Molecular detection of t(8;21)/AML1-ETO in AML M1/M2: correlation with cytogenetics, morphology and immunophenotype. Br J Haematol. 1996; 92(4):855-65 [PubMed] Related Publications
The t(8;21) identifies a subgroup of acute myeloid leukaemia (AML) with a relatively good prognosis which may merit different treatment. It is associated predominantly, but not exclusively, with AML M2, and corresponds to rearrangements involving the AML1 and ETO genes. AML1-ETO positive, t(8;21) negative cases are well recognized but their incidence is unknown. In order to determine optimal prospective AML1-ETO RT-PCR screening strategies, we analysed 64 unselected AML M1 and M2 cases and correlated the results with other biological parameters. Molecular screening increased the overall detection rate from 8% to 14%. AML1-ETO was found in 3% (1/32) of AML M1 and 25% (8/32) of M2, including three patients without a classic (8;21) but with chromosome 8 abnormalities. It was more common in younger patients. Correlation with morphology enabled development of a scoring system which detected all nine AML1-ETO-positive cases with a false positive rate of 7% (4/55). Although certain AML1-ETO-positive cases demonstrated characteristic immunological features (CD19 and CD34 expression, CD33 negativity), each of these markers was insufficiently specific to permit prediction in an individual case. We conclude that initial routine prospective molecular screening for AML1-ETO in all AMLs, combined with standardized morphological and immunological analysis, is desirable in order to produce improved prognostic stratification and to determine whether screening can ultimately be restricted to appropriate subgroups.
Rubin CM, Larson RA, Anastasi J, et al. t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood. 1990; 76(12):2594-8 [PubMed] Related Publications
We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.