A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene
ABSTRACT NF1 inactivation occurs in specific human cancers, including juvenile myelomonocytic leukemia, an aggressive myeloproliferative disorder of childhood. However, evidence suggests that Nf1 loss alone does not cause leukemia. We therefore hypothesized that inactivation of the Nf1 tumor suppressor gene requires cooperating mutations to cause acute leukemia. To search for candidate genes that cooperate with Nf1 deficiency in leukemogenesis, we performed a forward genetic screen using retroviral insertion mutagenesis in Nf1 mutant mice. We identified 43 common proviral insertion sites that contain candidate genes involved in leukemogenesis. One of these genes, Bcl11a, confers a growth advantage in cultured Nf1 mutant hematopoietic cells and causes early onset of leukemia of either myeloid or lymphoid lineage in mice when expressed in Nf1-deficient bone marrow. Bcl11a-expressing cells display compromised p21(Cip1) induction, suggesting that Bcl11a's oncogenic effects are mediated, in part, through suppression of p21(Cip1). Importantly, Bcl11a is expressed in human chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia samples. A subset of AML patients, who had poor outcomes, of 16 clusters, displayed high levels of BCL11A in leukemic cells. These findings suggest that deregulated Bcl11a cooperates with Nf1 in leukemogenesis, and a therapeutic strategy targeting the BCL11A pathway may prove beneficial in the treatment of leukemia.
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ABSTRACT: The results of a previous study showed that a clear dysregulation was evident in the global gene expression of the BCL11A-suppressed B-lymphoma cells. In this study, the bone morphogenetic protein receptor, type II (BMPR2), E1A binding protein p300 (EP300), transforming growth factor-β2 (TGFβ2), and tumor necrosis factor, and alpha-induced protein 3 (TNFAIP3) gene expression patterns in B-cell malignancies were studied.
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ABSTRACT: Triple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies.Nature Communications 01/2015; 6:5987. DOI:10.1038/ncomms6987 · 10.74 Impact Factor
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ABSTRACT: Our previous study has shown that downregulation of B-cell chronic lymphocytic leukemia (CLL)/lymphoma11A (BCL11A) gene by small interfering RNA (siRNA) results in the growth inhibition and apoptosis of B cell lymphoma cell line SUDHL6. To gain further insight into the molecular mechanisms of this process and identify the differentially expressed genes in SUDHL6 cells after BCL11A downregulation, the global gene expression profile was identified and analyzed using the Affymetrix HG-U133 Plus 2.0 array.Twenty-one differentially expressed genes were validated and analyzed from the BCL11 A siRNA-treated SUDHL6 cells. There was a significant dysregulation in the global gene expression of the BCL11A-suppressed SUDHL6 cells.There were 1903 genes differentially expressed between the BCL11 A siRNA- and negative control-transfected cells. Of these, there were 916 upregulated genes and 987 downregulated genes. The differential genes are involved in various molecular functions and signalling pathways. QRT-PCR validation of the selected differentially expressed genes demonstrated there was a good correlation with the microarray analysis. There is a significant deregulation of expression in the apoptosis-related genes such as BCL-2, BCL2L11 and involved in TGFβ, MAPK, WNT signalling pathways after BCL11A was downregulated in SUDHL6 cells . Our results show that the suppression of BCL11A by RNA interference altered gene expression profile of SUDHL6 cells. The apoptosis-related genes BCL-2 , BCL2L11 and the gene alterations in TGFβ, MAPK, WNT signalling pathways might be important in BCL11A siRNA-induced apoptosis of SUDHL6 cells, suggesting BCL11A is involved in gene networks associated with apoptosis.Cell Biology International 07/2014; DOI:10.1002/cbin.10332 · 1.64 Impact Factor