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Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE137662 | GEO | 2019/12/05

REPOSITORIES: GEO

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Chromatin topology reorganization and transcription repression by PML-RAR? in acute promyeloid leukemia.

Project description:BACKGROUND:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RAR?, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RAR? in leukemogenesis remain largely unknown. RESULTS:Using an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RAR? induction and perform additional analyses in patient-derived APL cells with native PML-RAR?. We discover that PML-RAR? mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factors binding at enhancers and super-enhancers, and leads to transcriptional repression of genes critical for myeloid differentiation and maturation. CONCLUSIONS:Our results not only provide novel topological insights for the roles of PML-RAR? in transforming myeloid cells into leukemia cells, but further uncover a topological framework of a molecular mechanism for oncogenic fusion proteins in cancers.

| S-EPMC7212609 | biostudies-literature

Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (RNA-seq)

Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.

2019-12-17 | GSE142198 | GEO

Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIP-seq)

2019-12-17 | GSE142197 | GEO

Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIA-PET)

2019-12-05 | GSE137661 | GEO

Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia

Project description:Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia

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Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIP-seq)

Project description:Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIP-seq)

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Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIA-PET)

Project description:Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIA-PET)

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Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (RNA-seq)

Project description:Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (RNA-seq)

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The PML domain of PML-RARα blocks senescence to promote leukemia.

Project description:In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.

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Transcriptional repression of CDKN2D by PML/RARα contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells.

Project description:Cell proliferation and differentiation are highly coordinated processes. These two processes are disrupted during leukemogenesis, resulting in differentiation block and uncontrolled proliferation in leukemia. To understand the mechanisms disrupting the coordination between the two processes in acute promyelocytic leukemia (APL), we investigated the regulatory mechanism of the negative cell cycle regulator CDKN2D by the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein and the role of CDKN2D in cell differentiation and proliferation. We found that CDKN2D expression in APL cells was significantly lower than that in normal promyelocytes. By chromatin immunoprecipitation and luciferase reporter assays, we showed that PML/RARα directly bound to and inhibited the transactivation of the CDKN2D promoter. Further evidence by the truncated and mutated CDKN2D promoters revealed that the everted repeat 8 (ER8) motif on the promoter was the binding site of PML/RARα. Forced expression of CDKN2D induced G0/G1 phase arrest and partial granulocytic differentiation in APL-derived NB4 cells, suggesting the function of CDKN2D in regulating both cell proliferation and granulocytic differentiation. Furthermore, all-trans retinoic acid (ATRA) significantly induced CDKN2D expression in APL cells and knockdown of CDKN2D expression during ATRA treatment partially blocked the ATRA-induced differentiation and cell cycle arrest. Collectively, our data indicate that CDKN2D repression by PML/RARα disrupts both cell proliferation and differentiation in the pathogenesis of APL, and induced expression of CDKN2D by ATRA alleviates the disruption of both processes to ensure treatment efficiency. This study provides a mechanism for coupling proliferation and differentiation in leukemic cells through the action of CDKN2D.

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