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

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

2023-01-30 | GSE196480 | GEO

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

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

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

| PRJNA805127 | ENA

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.

2024-08-14 | GSE274558 | GEO

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

Prolonged XPO1 inhibition is essential to achieve optimal antileukemic activity in NPM1-mutated acute myeloid leukemia

Project description:NPM1-mutated acute myeloid leukemia (AML) accounts for one third of AML in adults. NPM1-mutated AML maintenance depends on the interaction between mutated NPM1 (NPM1c) and the nuclear exporter Exportin 1 (XPO1). In this work, we show that continous XPO1 inhibition is necessary to achieve stable disruption of the NPM1c-XPO1 interaction and to induce HOX downregulation and differentiation of AML cells with mutated NPM1. In contrast, intermittent XPO1 inhibition only results in minimal transcriptional perturbation and limited antileukemic activity.

2022-09-21 | GSE181176 | GEO

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