Gene Summary

Gene:TAL1; TAL bHLH transcription factor 1, erythroid differentiation factor
Aliases: SCL, TCL5, tal-1, bHLHa17
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-cell acute lymphocytic leukemia protein 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (45)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Cancer Gene Expression Regulation
  • Metalloproteins
  • Immunophenotyping
  • Infant
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • TAL1
  • Adult T-Cell Leukemia-Lymphoma
  • Sequence Deletion
  • Base Sequence
  • LIM Domain Proteins
  • Oncogene Fusion Proteins
  • Childhood Cancer
  • Gene Deletion
  • Transcription Factor 3
  • Gene Expression Profiling
  • Hematopoiesis
  • Adolescents
  • Gene Rearrangement
  • Homeodomain Proteins
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neoplastic Cell Transformation
  • Helix-Loop-Helix Motifs
  • Leukaemia
  • Chromosome 1
  • Leukemic Gene Expression Regulation
  • Basic Helix-Loop-Helix Transcription Factors
  • Promoter Regions
  • Cell Differentiation
  • DNA-Binding Proteins
  • Messenger RNA
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Acute Lymphocytic Leukaemia
  • Polymerase Chain Reaction
  • Signal Transducing Adaptor Proteins
  • Mutation
  • Neoplasm Proteins
  • Proto-Oncogenes
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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

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

Latest Publications: TAL1 (cancer-related)

Kidoya H, Muramatsu F, Shimamura T, et al.
Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis.
Nat Commun. 2019; 10(1):1072 [PubMed] Free Access to Full Article Related Publications
The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA. In addition, we found that dysfunction of Regnase-1 leads to the rapid onset of abnormal hematopoiesis. Thus, our data reveal that Regnase-1-mediated post-transcriptional regulation is required for HSPC maintenance and suggest that it represents a leukemia tumor suppressor.

Cao S, Zheng J, Liu X, et al.
FXR1 promotes the malignant biological behavior of glioma cells via stabilizing MIR17HG.
J Exp Clin Cancer Res. 2019; 38(1):37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence has highlighted the potential role of RNA binding proteins (RBPs) in the biological behaviors of glioblastoma cells. Herein, the expression and function of RNA binding proteins FXR1 were investigated in human glioma cells.
METHODS: Quantitative real-time PCR were conducted to evaluate the expression of MIR17HG and miR-346, miRNA-425-5p in glioma tissues and cells. Western blot were used to explore the expression of FXR1, TAL1 and DEC1 in glioma tissues and cells. Stable knockdown of FXR1 and MIR17HG in glioma cells were established to explore the function of FXR1, MIR17HG in glioma cells. Further, RIP and RNA pull-down assays were used to investigate the correlation between FXR1 and MIR17HG. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate the function of FXR1 and MIR17HG in malignant biological behaviors of glioma cells. ChIP assays were employed to ascertain the correlations between TAL1 and MIR17HG.
RESULTS: FXR1and MIR17HG were upregulated in glioma tissues and cell lines. Downregulation of FXR1 or MIR17HG resulted in inhibition of glioma cells progression. We also found that FXR1 regulates the biological behavior of glioma cells via stabilizing MIR17HG. In addition, downregulated MIR17HG increased miR-346/miR-425-5p expression and MIR17HG acted as ceRNA to sponge miR-346/miR-425-5p. TAL1 was a direct target of miR-346/miR-425-5p, and played oncogenic role in glioma cells. More importantly, TAL1 activated MIR17HG promoter and upregulated its expression, forming a feedback loop. Remarkably, FXR1 knockdown combined with inhibition of MIR17HG resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo.
CONCLUSIONS: FXR1/MIR17HG/miR-346(miR-425-5p)/TAL1/DEC1 axis plays a novel role in regulating the malignant behavior of glioma cells, which may be a new potential therapeutic strategy for glioma therapy.

Wu X, Xiao Y, Yan W, et al.
The human oncogene SCL/TAL1 interrupting locus (STIL) promotes tumor growth through MAPK/ERK, PI3K/Akt and AMPK pathways in prostate cancer.
Gene. 2019; 686:220-227 [PubMed] Related Publications
The morbidity and mortality of prostate cancer (PCa) in China have increased obviously, which became the second leading cause of death in men with cancer. Hedgehog (Hh) signaling pathway is a key signaling pathway involved in the prostate cancer progression. The human oncogene SCL/TAL1 interrupting locus (STIL) can modulate the Hh signaling pathway, but its function in PCa has not been reported. Here, we showed that STIL was increased in high grade prostate cancer tissue. Knockdown of STIL in prostate cancer cells PC-3 and DU 145 significantly decreased the proliferation of cells and induced cellular apoptosis through casepase3/7 mediated pathway. Moreover, the colony formation ability was also inhibited when knockdown of STIL by lentivirus-mediated shRNA. Furthermore, the cellular signaling antibody array analysis revealed which signaling pathway was affected when silencing STIL. Altogether, we found that STIL could affect MAPK/ERK, PI3K/Akt and AMPK signaling pathways, thus promoting cellular proliferation, colony formation and suppressing cellular apoptosis in prostate cancer.

Tan TK, Zhang C, Sanda T
Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia.
Int J Hematol. 2019; 109(1):5-17 [PubMed] Related Publications
TAL1/SCL is a prime example of an oncogenic transcription factor that is abnormally expressed in acute leukemia due to the replacement of regulator elements. This gene has also been recognized as an essential regulator of hematopoiesis. TAL1 expression is strictly regulated in a lineage- and stage-specific manner. Such precise control is crucial for the switching of the transcriptional program. The misexpression of TAL1 in immature thymocytes leads to a widespread series of orchestrated downstream events that affect several different cellular machineries, resulting in a lethal consequence, namely T-cell acute lymphoblastic leukemia (T-ALL). In this article, we will discuss the transcriptional regulatory network and downstream target genes, including protein-coding genes and non-coding RNAs, controlled by TAL1 in normal hematopoiesis and T-cell leukemogenesis.

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.

Gustafsson BM, Mattsson K, Bogdanovic G, et al.
Origins of STIL-TAL1 fusion genes in children who later developed paediatric T-cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots.
Pediatr Blood Cancer. 2018; 65(11):e27310 [PubMed] Related Publications
SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.

Cordas Dos Santos DM, Eilers J, Sosa Vizcaino A, et al.
MAP3K7 is recurrently deleted in pediatric T-lymphoblastic leukemia and affects cell proliferation independently of NF-κB.
BMC Cancer. 2018; 18(1):663 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Deletions of 6q15-16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4.
METHODS: MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR.
RESULTS: MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α.
CONCLUSIONS: This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts.

Jenkins CE, Gusscott S, Wong RJ, et al.
RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.
Exp Hematol. 2018; 64:84-96 [PubMed] Related Publications
RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1, along with transcription factors TAL1 and NOTCH1, as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis. RUNX1 upregulated variable sets of target genes in each cell line, but consistently included a core set of oncogenic effectors including insulin-like growth factor 1 receptor (IGF1R) and NRAS. Our results support the conclusion that RUNX1 has a net positive effect on cell growth in the context of established T-ALL.

Ngoc PCT, Tan SH, Tan TK, et al.
Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia.
Leukemia. 2018; 32(10):2138-2151 [PubMed] Related Publications
TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 and its regulatory partners (GATA3, RUNX1, and MYB) positively regulate each other and coordinately regulate the expression of their downstream target genes in T-ALL cells. However, long non-coding RNAs (lncRNAs) regulated by these factors are largely unknown. Here we established a bioinformatics pipeline and analyzed RNA-seq datasets with deep coverage to identify lncRNAs regulated by TAL1 in T-ALL cells. Our analysis predicted 57 putative lncRNAs that are activated by TAL1. Many of these transcripts were regulated by GATA3, RUNX1, and MYB in a coordinated manner. We identified two novel transcripts that were activated in multiple T-ALL cell samples but were downregulated in normal thymocytes. One transcript near the ARID5B gene locus was specifically expressed in TAL1-positive T-ALL cases. The other transcript located between the FAM49A and MYCN gene locus was also expressed in normal hematopoietic stem cells and T-cell progenitor cells. In addition, we identified a subset of lncRNAs that were negatively regulated by TAL1 and positively regulated by E-proteins in T-ALL cells. This included a known lncRNA (lnc-OAZ3-2:7) located near the RORC gene, which was expressed in normal thymocytes but repressed in TAL1-positive T-ALL cells.

Furness CL, Mansur MB, Weston VJ, et al.
The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia.
Leukemia. 2018; 32(9):1984-1993 [PubMed] Free Access to Full Article Related Publications
Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.

Leong WZ, Tan SH, Ngoc PCT, et al.
ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis.
Genes Dev. 2017; 31(23-24):2343-2360 [PubMed] Free Access to Full Article Related Publications
The oncogenic transcription factor

Chen B, Jiang L, Zhong ML, et al.
Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia.
Proc Natl Acad Sci U S A. 2018; 115(2):373-378 [PubMed] Free Access to Full Article Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with

Bornschein S, Demeyer S, Stirparo R, et al.
Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system.
Leukemia. 2018; 32(4):941-951 [PubMed] Free Access to Full Article Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.

Dackus GM, Ter Hoeve ND, Opdam M, et al.
Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study.
BMJ Open. 2017; 7(11):e017842 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged
METHODS AND ANALYSIS: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle.
ETHICS AND DISSEMINATION: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

Zhu M, Liu C, Li S, et al.
Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer.
Sci Rep. 2017; 7(1):11399 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Many patients suffer from bone metastasis. Sclerostin, a key regulator of normal bone remodeling, is critically involved in osteolytic bone diseases. However, its role in breast cancer bone metastasis remains unknown. Here, we found that sclerostin was overexpressed in breast cancer tumor tissues and cell lines. Inhibition of sclerostin by antibody (Scl-Ab) significantly reduced migration and invasion of MDA-MB-231 and MCF-7 cells in a time- and dose-dependent manner. In xenograft model, sclerostin inhibition improved survival of nude mice and prevented osteolytic lesions resulting from tumor metastasis. Taken together, sclerostin promotes breast cancer cell migration, invasion and bone osteolysis. Inhibition of sclerostin may serve as an efficient strategy for interventions against breast cancer bone metastasis or osteolytic bone diseases.

Shahrabi S, Khodadi E, Saba F, et al.
Sex chromosome changes in leukemia: cytogenetics and molecular aspects.
Hematology. 2018; 23(3):139-147 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Sex chromosome loss (SCL) can occur in older men as a physiological phenomenon or as an acquired abnormality in leukemia. Loss of chromosome Y and loss of chromosome X are acquired disorders that are mainly observed in patients over 80 years as well as in myeloid and lymphoid malignancies. In this review, we examine the cytogenetic and molecular changes of sex chromosomes in leukemia.
METHODS: Relevant English language literature were searched and retrieved from PubMed search engine (1990-2016). The following keywords were used: 'Sex chromosomes', 'Leukemia' and 'Cytogenetics'.
RESULTS: The loss of tumor suppressor genes along with these chromosomal abnormalities in the majority of malignant cells in bone marrow (BM) has raised the question whether this is an age-related phenomenon or has occurred as a result of clonal abnormality. On the other hand, the presence of these chromosomal abnormalities in a number of genetic diseases associated with leukemia leads to progression of malignancy, and their role in peripheral blood stem cell transplantation confirm the finding that these chromosomal abnormalities can play an important role in clonal abnormality.
CONCLUSION: The presence of these abnormalities can cause genetic instability in BM and result in the development of a malignant clone and progression of the disease. In addition, the evaluation of SCL together with the genes involved in these chromosomes can contribute to predict the disease prognosis as well as monitoring of malignancy.

Kalender Atak Z, Imrichova H, Svetlichnyy D, et al.
Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks.
Genome Med. 2017; 9(1):80 [PubMed] Free Access to Full Article Related Publications
The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying "personal" gene regulatory network. We validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genomes of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers. μ-cisTarget is available from http://mucistarget.aertslab.org .

Choi A, Illendula A, Pulikkan JA, et al.
RUNX1 is required for oncogenic
Blood. 2017; 130(15):1722-1733 [PubMed] Free Access to Full Article Related Publications
The gene encoding the RUNX1 transcription factor is mutated in a subset of T-cell acute lymphoblastic leukemia (T-ALL) patients, and

Zhao X, Hong Y, Qin Y, et al.
The clinical significance of monitoring the expression of the SIL-TAL1 fusion gene in T-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.
Int J Lab Hematol. 2017; 39(6):613-619 [PubMed] Related Publications
INTRODUCTION: SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL). However, whether this fusion gene might be used as a reliable marker of minimal residual disease (MRD) following allogeneic stem cell transplantation (allo-HSCT) remains unknown METHODS: The clinical data of consecutive 29 patients with T-ALL who received allo-HSCT were collected. Their MRD were evaluated by SIL-TAL1, Wilms' tumor 1 (WT1) expression, and the leukemia-associated immunophenotype (LAIP) .
RESULTS: The median follow-up was 354 days (71-2111 days). Of the enrolled patients, 14 (87.5%) patients died of leukemia relapse. A total of 15 (51.7%) patients experienced relapse at a median of 90 days (60-540 days) after transplantation. The SIL-TAL1 expression of 16 patients converted from negative prior to transplantation to positive at 77 days (30-281 days) following transplantation; furthermore, 15 (93.8%) of them eventually experienced relapse. In the 15 relapsed patients, 13 (86.7%) had increased SIL-TAL1 expression levels 30 days (11-220 days) earlier than the hematological relapse and the detection of abnormal WT1 and LAIP.
CONCLUSION: We are the first to demonstrate the reliability of the SIL-TAL1 fusion gene as a good MRD marker for patients with T-ALL after allo-HSCT.

Ko JS, Daniels B, Emanuel PO, et al.
Spindle Cell Lipomas in Women: A Report of 53 Cases.
Am J Surg Pathol. 2017; 41(9):1267-1274 [PubMed] Related Publications
Spindle cell lipomas (SCL) are typically tumors of the upper back/neck (shawl region) of men (80% to 90%). In general, there is a frequent tendency to restrict the diagnosis to this specific clinical scenario and a hesitancy to diagnose SCL in women. We hypothesized that SCL in women have a more varied presentation. A total of 395 SCL were diagnosed at our institution over the last 11 years. The diagnosis of SCL in women was confirmed by re-review. Immunohistochemical stains for CD34, desmin, estrogen receptor, and p16 were performed. In a subset, fluorescence in situ hybridization to detect Retinoblastoma1 (RB1) gene deletion was performed. Of 395 SCLs, 331 (86%) occurred in men; 53 (14%) occurred in women (11 cases excluded). Of the 64 SCL in women, 58 had available material. In total, 53 of 58 were confirmed as SCL. Women were younger at diagnosis (median, 51 y; range, 5 to 76 y) compared with men (64 y; range, 23 to 98 y), P<0.0001, t test. SCL in women typically occurred outside the shawl distribution (36/53, 68%) compared with men (95/331, 29%) (P<0.001), including extremities (16/53, 30% vs. 32/331, 10%) and face (11/53, 21% vs. 47/331, 14%). Dermal SCL in women were also relatively common (16/53, 30%). The cases demonstrated varying proportions of bland spindled cells, ropey collagen, myxoid matrix, and adipocytes. By immunohistochemistry, 46/46 were CD34, 48 of 48 were desmin negative, 33 of 42 were estrogen receptor negative, and 29 of 42 had loss of p16 expression. In total, 12 of 14 showed RB1 loss by fluorescence in situ hybridization. SCL in women frequently occurs in unconventional locations and in at a slightly younger patient age.

Liu Y, Easton J, Shao Y, et al.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.
Nat Genet. 2017; 49(8):1211-1218 [PubMed] Free Access to Full Article Related Publications
Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.

Sanda T, Leong WZ
TAL1 as a master oncogenic transcription factor in T-cell acute lymphoblastic leukemia.
Exp Hematol. 2017; 53:7-15 [PubMed] Related Publications
In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with nonhematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia. A prime example is T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder characterized by clonal proliferation of immature stage thymocytes. Although a relatively small number of genetic abnormalities are observed in T-ALL, these abnormalities are crucial for leukemogenesis. Many oncogenes and tumor suppressors in T-ALL are transcription factors that are required for normal hematopoiesis. The transformation process in T-ALL is efficient and orchestrated; the oncogene disrupts the transcriptional program directing T-cell differentiation and also uses its native ability as a master transcription factor in hematopoiesis. This imbalance in the transcriptional program is a primary determinant underlying the molecular pathogenesis of T-ALL. In this review, we focus on the oncogenic transcription factor TAL1 and the tumor-suppressor E-proteins and discuss the malignant cell state, the transcriptional circuit, and the consequence of molecular abnormalities in T-ALL.

Busse TM, Roth JJ, Wilmoth D, et al.
Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients.
Genes Chromosomes Cancer. 2017; 56(10):730-749 [PubMed] Related Publications
Gene fusions resulting from structural rearrangements are an established mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350 single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211 pediatric cancer patients were evaluated for copy number alterations (CNAs) associated with gene fusions. Karyotype or fluorescence in situ hybridization studies were performed in 42% of the patients. Ten percent of the bone marrow or solid tumor specimens had SNP array-associated CNAs suggestive of a gene fusion. Alterations involving ETV6, ABL1-NUP214, EBF1-PDGFRB, KMT2A(MLL), LMO2-RAG, MYH11-CBFB, NSD1-NUP98, PBX1, STIL-TAL1, ZNF384-TCF3, P2RY8-CRLF2, and RUNX1T1-RUNX1 fusions were detected in the bone marrow samples. The most common alteration among the low-grade gliomas was a 7q34 tandem duplication resulting in a KIAA1549-BRAF fusion. Additional fusions identified in the pediatric brain tumors included FAM131B-BRAF and RAF1-QKI. COL1A1-PDGFB, CRTC1-MAML2, EWSR1, HEY1, PAX3- and PAX7-FOXO1, and PLAG1 fusions were determined in a variety of solid tumors and a novel potential gene fusion, FGFR1-USP6, was detected in an aneurysmal bone cyst. The identification of these gene fusions was instrumental in tumor diagnosis. In contrast to hematologic and solid tumors in adults that are predominantly driven by mutations, the majority of hematologic and solid tumors in children are characterized by CNAs and gene fusions. Chromosomal microarray analysis is therefore a robust platform to identify diagnostic and prognostic markers in the clinical setting.

Michal M, Kazakov DV, Hadravsky L, et al.
Lipoblasts in spindle cell and pleomorphic lipomas: a close scrutiny.
Hum Pathol. 2017; 65:140-146 [PubMed] Related Publications
The presence and frequency of lipoblasts (LPB) in spindle cell lipomas (SCL) and pleomorphic lipomas (PL) has never been studied in detail on a histologically, immunohistochemically and molecular genetically validated set of tumors. The authors investigated this feature by reviewing 91 cases of SCL and 38 PL. When more than 3 unequivocal LPB were found, the case was regarded as positive for the presence of LPB. All positive cases were then stained with CD34 and retinoblastoma (Rb) protein antibodies and tested by fluorescence in situ hybridization for MDM2 and CDK4 amplifications and the FUS gene rearrangements. The patients with SCL and PL containing LPB were 14 women and 47 men, the rest were of unknown gender. The cases usually presented as superficial, well-circumscribed soft tissue masses and most commonly occurred in the upper back and neck. CD34 was expressed in all cases, while Rb protein was consistently absent in all. Molecular genetic results, when available, were in concordance with the morphological diagnosis of SCL/PL. LPB were found in 37 (41%) cases of SCL and 25 cases of PL (66%). While in many cases they are inconspicuous, in some others they constitute a very prominent component of the tumor. It is important to be aware of this fact in order to avoid misinterpretation as liposarcoma.

Tesio M, Trinquand A, Ballerini P, et al.
Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.
Leukemia. 2017; 31(12):2594-2600 [PubMed] Related Publications
The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

Delgado-Calle J, Anderson J, Cregor MD, et al.
Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth.
Leukemia. 2017; 31(12):2686-2694 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl), an osteocyte-derived inhibitor of Wnt/β-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost, the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost/Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro. These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM, suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM.

Liau WS, Ngoc PC, Sanda T
Roles of the RUNX1 Enhancer in Normal Hematopoiesis and Leukemogenesis.
Adv Exp Med Biol. 2017; 962:139-147 [PubMed] Related Publications
Enhancers are regulatory elements in genomic DNA that contain specific sequence motifs that are bound by DNA-binding transcription factors. The activity of enhancers is tightly regulated in an integrated and combinatorial manner, thus yielding complex patterns of transcription in different tissues. Identifying enhancers is crucial to understanding the physiological and pathogenic roles of their target genes. The RUNX1 intronic enhancer, eR1, acts in cis to regulate RUNX1 gene expression in hematopoietic stem cells (HSCs) and hemogenic endothelial cells. RUNX1 and other hematopoietic transcription factors TAL1/SCL, GATA2, PU.1, LMO2 and LDB1 bind at this region. Interestingly, recent studies have revealed that this region is involved in a large cluster of enhancers termed a super-enhancer. The RUNX1 super-enhancer is observed in normal HSCs and T-cell acute lymphoblastic leukemia cells. In this review, we describe the discovery of eR1 and its roles in normal development and leukemogenesis, as well as its potential applications in stem cell research.

Rivera-Reyes A, Hayer KE, Bassing CH
Genomic Alterations of Non-Coding Regions Underlie Human Cancer: Lessons from T-ALL.
Trends Mol Med. 2016; 22(12):1035-1046 [PubMed] Free Access to Full Article Related Publications
It has been appreciated for decades that somatic genomic alterations that change coding sequences of proto-oncogenes, translocate enhancers/promoters near proto-oncogenes, or create fusion oncogenes can drive cancer by inducing oncogenic activities. An explosion of genome-wide technologies over the past decade has fueled discoveries of the roles of three-dimensional chromosome structure and powerful cis-acting elements (super-enhancers) in regulating gene transcription. In recent years, studies of human T cell acute lymphoblastic leukemia (T-ALL) using genome-wide technologies have provided paradigms for how non-coding genomic region alterations can disrupt 3D chromosome architecture or establish super-enhancers to activate oncogenic transcription of proto-oncogenes. These studies raise important issues to consider with the objective of leveraging basic knowledge into new diagnostic and therapeutic opportunities for cancer patients.

Fujiwara T, Sasaki K, Saito K, et al.
Forced FOG1 expression in erythroleukemia cells: Induction of erythroid genes and repression of myelo-lymphoid transcription factor PU.1.
Biochem Biophys Res Commun. 2017; 485(2):380-387 [PubMed] Related Publications
The transcription factor GATA-1-interacting protein Friend of GATA-1 (FOG1) is essential for proper transcriptional activation and repression of GATA-1 target genes; yet, the mechanisms by which FOG1 exerts its activating and repressing functions remain unknown. Forced FOG1 expression in human K562 erythroleukemia cells induced the expression of erythroid genes (SLC4A1, globins) but repressed that of GATA-2 and PU.1. A quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated increased GATA-1 chromatin occupancy at both FOG1-activated as well as FOG1-repressed gene loci. However, while TAL1 chromatin occupancy was significantly increased at FOG1-activated gene loci, it was significantly decreased at FOG1-repressed gene loci. When FOG1 was overexpressed in TAL1-knocked down K562 cells, FOG1-mediated activation of HBA, HBG, and SLC4A1 was significantly compromised by TAL1 knockdown, suggesting that FOG1 may require TAL1 to activate GATA-1 target genes. Promoter analysis and quantitative ChIP analysis demonstrated that FOG1-mediated transcriptional repression of PU.1 would be mediated through a GATA-binding element located at its promoter, accompanied by significantly decreased H3 acetylation at lysine 4 and 9 (K4 and K9) as well as H3K4 trimethylation. Our results provide important mechanistic insight into the role of FOG1 in the regulation of GATA-1-regulated genes and suggest that FOG1 has an important role in inducing cells to differentiate toward the erythroid lineage rather than the myelo-lymphoid one by repressing the expression of PU.1.

Porcher C, Chagraoui H, Kristiansen MS
SCL/TAL1: a multifaceted regulator from blood development to disease.
Blood. 2017; 129(15):2051-2060 [PubMed] Related Publications
SCL/TAL1 (stem cell leukemia/T-cell acute lymphoblastic leukemia [T-ALL] 1) is an essential transcription factor in normal and malignant hematopoiesis. It is required for specification of the blood program during development, adult hematopoietic stem cell survival and quiescence, and terminal maturation of select blood lineages. Following ectopic expression, SCL contributes to oncogenesis in T-ALL. Remarkably, SCL's activities are all mediated through nucleation of a core quaternary protein complex (SCL:E-protein:LMO1/2 [LIM domain only 1 or 2]:LDB1 [LIM domain-binding protein 1]) and dynamic recruitment of conserved combinatorial associations of additional regulators in a lineage- and stage-specific context. The finely tuned control of SCL's regulatory functions (lineage priming, activation, and repression of gene expression programs) provides insight into fundamental developmental and transcriptional mechanisms, and highlights mechanistic parallels between normal and oncogenic processes. Importantly, recent discoveries are paving the way to the development of innovative therapeutic opportunities in SCL

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