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Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [SLAM-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: GSE196479 | GEO | 2023/01/30

REPOSITORIES: GEO

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Mutant NPM1 binds chromatin and directly regulates oncogenic transcription in acute myeloid leukemia [ChIP-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 | GSE196476 | GEO

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

2023-01-30 | GSE196478 | 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

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

2023-01-30 | GSE196480 | GEO

Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia.

Project description:The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Around half of patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncoprotein mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene-expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small-molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.SignificanceWe uncovered an important functional role of mutant NPM1 as a crucial direct driver of oncogenic gene expression in AML. NPM1c can bind to chromatin and cooperate with the MLL complex, providing the first functional insight into the mechanism of Menin-MLL inhibition in NPM1c leukemias. See related article by Wang et al., p. 724. This article is highlighted in the In This Issue feature, p. 517.

| S-EPMC10084473 | biostudies-literature

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

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

| PRJNA805170 | ENA

Mutant NPM1 marginally impacts translation in AML cells

Project description:Combining RNA-seq, Ribo-seq and selective NPM1c degradation through dTAG-13, we explored for the first time the impact of NPM1c on ribosome footprint in the two available NPM1-mutated cell lines. Analysis of translatome showed that NPM1c only marginally impacts ribosome abundance and positioning on mRNA in NPM1-mutated cells.

2024-09-30 | GSE251919 | 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

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