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BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE147798 | GEO | 2021/12/21

REPOSITORIES: GEO

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BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [array]

Project description:The transcriptional repressor Bcl11a is involved in hematological malignancies, B-cell development and fetal to adult hemoglobin switching, however, the molecular mechanism how Bcl11a promotes development of myeloid leukemia remains largely unknown. We found that Bcl11a cooperates with the pseudokinase Trib1 in AML development. Bcl11a promotes proliferation of Trib1-expressing AML cells both in vitro and in vivo. ChIP-seq analysis showed that Bcl11a is significantly associated on DNA-binding with PU.1 that promotes myeloid differentiation, and Bcl11a represses a number of PU.1 target genes such as Clec5a, Fcgr3 and Csf1r. The repression of PU.1 target genes by Bcl11a is achieved by both sequence-specific DNA binding activity and recruitment of corepressors by Bcl11a, and suppression of corepressor components HDAC1 and LSD1 cancelled the repressive activity. Association of high level of expression of BCL11A and worse prognosis is observed in human AML patients, and blocking of BCL11A expression upregulates PU.1 target expression, inhibits engraftment to bone marrow, and enhances myeloid differentiation of HL-60 cells, suggesting that BCL11A is involved in human myeloid malignancies via the PU.1 transcriptional activity. We used microarrays to detail the global program of gene expression in mouse AML

2021-12-21 | GSE147797 | GEO

BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [ChIP-seq]

2021-12-21 | GSE147787 | GEO

BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes.

Project description:The transcriptional repressor BCL11A is involved in hematological malignancies, B-cell development, and fetal-to-adult hemoglobin switching. However, the molecular mechanism by which it promotes the development of myeloid leukemia remains largely unknown. We find that Bcl11a cooperates with the pseudokinase Trib1 in the development of acute myeloid leukemia (AML). Bcl11a promotes the proliferation and engraftment of Trib1-expressing AML cells in vitro and in vivo. Chromatin immunoprecipitation sequencing analysis showed that, upon DNA binding, Bcl11a is significantly associated with PU.1, an inducer of myeloid differentiation, and that Bcl11a represses several PU.1 target genes, such as Asb2, Clec5a, and Fcgr3. Asb2, as a Bcl11a target gene that modulates cytoskeleton and cell-cell interaction, plays a key role in Bcl11a-induced malignant progression. The repression of PU.1 target genes by Bcl11a is achieved by sequence-specific DNA-binding activity and recruitment of corepressors by Bcl11a. Suppression of the corepressor components HDAC and LSD1 reverses the repressive activity. Moreover, treatment of AML cells with the HDAC inhibitor pracinostat and the LSD1 inhibitor GSK2879552 resulted in growth inhibition in vitro and in vivo. High BCL11A expression is associated with worse prognosis in humans with AML. Blocking of BCL11A expression upregulates the expression of PU.1 target genes and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

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BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1

Project description:BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1

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BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [array]

Project description:BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [array]

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BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [ChIP-seq]

Project description:BCL11A promotes myeloid leukemogenesis by abrogating the transcriptional activity of PU.1 [ChIP-seq]

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The transcriptional repressor BCL11A promotes breast cancer metastasis.

Project description:The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6 Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.

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NAT10-mediated mRNA N4-acetylcitidine (ac4C) Promotes Stemness and Leukemogenesis in Acute Myeloid Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

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Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia.

Project description:Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction.

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Redistribution of PU.1 partner transcription factor RUNX1 binding secures cell survival during leukemogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-11-15 | GSE251674 | GEO