Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations

Abbas, Saman; Sanders, Mathijs A.; Zeilemaker, Annelieke; Geertsma-Kleinekoort, W M C; Koenders, Jasper E.; Kavelaars, François G.; Abbas, Zabiollah G.; Mahamoud, Souad; Chu, Isabel W. T.; Hoogenboezem, Remco M.; Peeters, Justine K.; Drunen, Ellen van; Galen, Janneke van; Beverloo, H. Berna; Löwenberg, Bob; Valk, Peter J.M.

doi:10.3324/haematol.2013.095604

Cited by 30 publications

(24 citation statements)

References 51 publications

(66 reference statements)

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“…In fact, the formation of super-enhancers in translocations may be a more common mechanism by which oncogenes are activated in AML and other types of cancer. In support of this, we recently showed that transposition of the B-Cell CLL/Lymphoma 11B (BCL11B) transcription factor locus into well-known super-enhancers resulted in overexpression of the BCL11B gene in several cases of AML (Abbas et al, 2014).…”

Section: Aberrant Evi1 Expression In Inv(3)/t(3;3) Aml and Cooperatinmentioning

confidence: 88%

“…In support of this, we recently showed that transposition of the B-Cell CLL/Lymphoma 11B (BCL11B) transcription factor locus into well-known super-enhancers resulted in overexpression of the BCL11B gene in several cases of AML (Abbas et al, 2014). In fact, the formation of super-enhancers in translocations may be a more common mechanism by which oncogenes are activated in AML and other types of cancer.…”

Section: Aberrant Evi1 Expression In Inv(3)/t(3;3) Aml and Cooperatinmentioning

confidence: 90%

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Review: Aberrant EVI1 expression in acute myeloid leukaemia

Hinai¹,

Valk²

2016

Br J Haematol

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Deregulated expression of the ecotropic virus integration site 1 (EVI1) gene is the molecular hallmark of therapy-resistant myeloid malignancies bearing chromosomal inv(3)(q21q26·2) or t(3;3)(q21;q26·2) [hereafter referred to as inv(3)/t(3;3)] abnormalities. EVI1 is a haematopoietic stemness and transcription factor with chromatin remodelling activity. Interestingly, the EVI1 gene also shows overexpression in 6-11% of adult acute myeloid leukaemia (AML) cases that do not carry any 3q aberrations. Deregulated expression of EVI1 is strongly associated with monosomy 7 and 11q23 abnormalities, which are known to be associated with poor response to treatment. However, EVI1 overexpression has been revealed as an important independent adverse prognostic marker in adult AML and defines distinct risk categories in 11q23-rearranged AML. Recently, important progress has been made in the delineation of the mechanism by which EVI1 becomes deregulated in inv(3)/t(3;3) as well as the cooperating mutations in this specific subset of AML with dismal prognosis.

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Section: Aberrant Evi1 Expression In Inv(3)/t(3;3) Aml and Cooperatinmentioning

confidence: 88%

Section: Aberrant Evi1 Expression In Inv(3)/t(3;3) Aml and Cooperatinmentioning

confidence: 90%

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Hinai¹,

Valk²

2016

Br J Haematol

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“…The pro-tumorigenic role of the ZEB2-BCL11B fusion has been previously linked to the overexpression of BCL11B [28,40]. Paraffin-embedded tissue was available for one of the patients carrying the chimera (#59810) and BCL11B expression was confirmed at protein level by immunohistochemistry ( Figure 3B).…”

Section: Bcl11b Protein Expression In Aml and Its Transcriptional Sigmentioning

confidence: 91%

Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia

Padella

Simonetti

Paciello

et al. 2019

Cancers

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Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML.

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“…In humans, chromosomal translocations involving the BCL11b gene locus were identified in patients with acute myeloid leukemia (AML), T-ALL and T/myeloid acute bilineage leukemia [[23]–[28]]. Likewise, deletions and missense mutations, disrupting gene function, were reported in 9 to 16% of pediatric T-ALL patients [[29],[30]].…”

Section: Introductionmentioning

confidence: 99%

Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients

et al. 2014

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BackgroundRisk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed.MethodsWe studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients.ResultsWe demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b.ConclusionsIn summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.

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Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations

Cited by 30 publications

References 51 publications

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Review: Aberrant EVI1 expression in acute myeloid leukaemia

Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia

Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients

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