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Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [PRO-seq]

ABSTRACT: We use an endogenously degrader tagged NPM1c leukemia cell line that allows rapid small molecule induced degradation to show that NPM1c occupies specific chromatin targets in AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196478 | GEO | 2023/01/30

REPOSITORIES: GEO

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Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [SLAM-seq]

Project description:We use an endogenously degrader tagged NPM1c leukemia cell line that allows rapid small molecule induced degradation to show that NPM1c occupies specific chromatin targets in AML.

2023-01-30 | GSE196479 | GEO

Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [RNA-seq]

2023-01-30 | GSE196477 | GEO

Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [ChIP-seq]

2023-01-30 | GSE196476 | GEO

Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia

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

2023-01-30 | GSE196480 | GEO

Cytoplasmic NPM1 maintains the leukemic state through HOX expression [ChIP-seq] 

Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

2018-08-06 | GSE111179 | GEO

Cytoplasmic NPM1 maintains the leukemic state through HOX expression [RNA-seq]  

2018-08-06 | GSE111178 | GEO

NPM1 mutation reprograms leukemic transcription network via reshaping TAD topology

Project description:C-terminal mutation of Nucleophosmin 1 (NPM1C+) was thought to be a primary driving event that reprograms leukemic-associated transcription program to transform hematopoietic stem and progenitor cells (HS/PCs). However, molecular mechanism underlying NPM1C+-driven leukemogenesis remain elusive. Here, we reported that NPM1C+ reprograms MIZ-1/MYC regulatory axis by altering NPM1-associated CTCF-driven topologically associated domains (TADs) that switched the balance of MIZ1 interaction with co-repressors MYC/G9A and coactivator p300 to control cell cycle progress and myeloid lineage-specific PU.1/CEBPa transcription networks. These alterations impaired hematopoietic cell cycle progression and myeloid differentiation. Knock-in of NPM1C+ in bone marrow HSPCs alters cell cycle regulators and myeloid master transcription factor (TF) TAD topology, chromatin accessibility, and gene regulation leading blockage of myeloid differentiation. Retention of NPM1 or reactivation of PU.1 or CEBPa within nucleus activates differentiation program by reorganizing TADs critical for myeloid TFs and cell cycle regulator, leading to blockage of NPM1C+-driven leukemogenesis. Thus, our data revealed that NPM1C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription program require for cell cycle progression and leukemic progression. Restoration of myeloid transcription program in nucleus reversed NPM1C+-driven transcription signature and promotes myeloid differentiation leading to mitigation of AML.

2023-08-09 | GSE208022 | GEO

Functionally distinct promoter classes initiate transcription via different mechanisms [PRO-Seq]

Project description:To identify the functional contribution to transcription of various promoter-bound proteins we have endogenously tagged select proteins with an auxin-inducible degron and measured nascent transcription with PRO-seq 6 hours after their depletion

2023-03-02 | GSE181257 | GEO

Whole cell proteome of U-2 OS cells with NPM1 and NPM1c overexpression

Project description:The nucleolar scaffold protein NPM1 acts as a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants that promote its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. In order to identify the proteome changes upon NPM1 and NPM1c overexpression, we performed TMT-labeled mass spectrometry analysis of whole cell lysates.

2023-11-20 | PXD040193 | Pride

Comprehensive comparison and biologic activity of novel therapeutic agents in NPM1 mutated Acute Myeloid Leukemia (AML)

Project description:Acute Myeloid Leukemia (AML) is frequently associated with mutations of NPM1 (NPM1c+) and even if considered to be of better prognosis for younger patients, relapse is frequent and outcome remains poor for elder patients with a need for novel treatment strategies. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) induce proteasomal degradation of NPM1c protein, NPM1 nuclear re localization, differentiation and apoptosis in NPM1c+ cells and blast clearance in relapsed/refractory AML patients. In line, the XPO1 inhibitor Selinexor showed similar results in vitro associated with down regulation of a specific HOX gene signature. BET inhibitors (BETi) OTX015 (MK-8628) and JQ1 yield antileukemic activity and here we demonstrate their effects in NPM1c+ leukemia cells compared to ATO+ATRA and Selinexor. Compared to ATO+ATRA and Selinexor, BRDi induced TP53 independent apoptosis, differentiation, proteasomal NPM1c degradation and nuclear relocalization in NPM1c+ OCI-AML3 cell line and to different extend in patient derived blast cells. As ATO+ATRA and Selinexor had significant biological activity in NPM1c+ cell line IMS-M2, these cells were resistant to BETi exposure, except for nuclear re localization of NPM1 which is a general phenomenon upon treatment with all three drug types. Gene profiling revealed that BRDi downregulate a BRD specific core gene signature in OCI-AML3 and IMS-M2 cells but IMS-M2 cells yield a transcriptional resistance signature including upregulation of the Wnt/beta-catenin pathway. HOX gene clusters in OCI-AML3 cells and IMS-M2 cells are heterogeneously regulated by BETi and are down regulated by ATO+ATRA in line with results reported for Selinexor treatment. Taken together, our preclinical results encourage clinical testing of ATO+ATRA, Selinexor and BRDi in NPM1c+ AML patients.

2020-06-01 | GSE146362 | GEO

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