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Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

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

ORGANISM(S): Mus musculus

PROVIDER: GSE133081 | GEO | 2025/03/01

REPOSITORIES: GEO

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Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:Purpose: Analysis of downstream pathways activated by NPMc+ and Flt3-ITD oncogenes in preleukemic hematopoietic stem cells (HSCs). Methods: RNA extracted and processed from MxCRE, Flt3-ITD and NPMc+/Flt3-ITD FACS sorted HSCs Results: These data demonstrate that NPMc+ expression in Flt3-ITD HSCs promote a transcriptional program that supports both self-renewal and quiescence.

2025-03-01 | GSE133077 | GEO

Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:Analysis of the transcriptional profile imposed by NPMc+ and Flt3-ITD oncogenes, both alone and in cooperation, on HSCs at single cell level

2025-03-01 | GSE133080 | GEO

Enforcement of stem-cell dormancy by nucleophosmin mutation is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:The most frequent mutation in AML patients with normal karyotype affects the Nucleophosmin gene (NPMc+). Different mouse models have shown that NPMc+ mutation can drive leukemia development. In this study, the impact of NPMc+ expression on the transcriptional program of mouse hematopietic stem cells (HSC) in vivo has been investigated.

2025-02-28 | GSE94650 | GEO

Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

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Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

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Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

Project description:Enforcement of stem-cell dormancy by NPMc+ is a critical determinant of unrestricted self-renewal during myeloid leukemogenesis

| PRJNA549913 | ENA

Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis.

Project description:It has become evident that acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells. Recent gene expression profile analysis of human leukemia stem cells and hematopoietic stem cell (HSC) populations identified a key transcriptional program shared by leukemia stem cells and HSC, which is associated with adverse outcomes in AML patients. One molecule that has been established as a pivotal regulator in fine-tuning of stem cell properties as well as a potent oncogenic determinant is ecotropic viral integration site 1 (EVI1). EVI1 is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of HSC self-renewal. This gene is notorious for its involvement in AML, as its activation confers extremely poor prognosis in patients with AML. Molecular analysis has identified a variety of gene products that are involved in HSC regulation as downstream targets or interacting proteins of EVI1. Thus, exploration of the molecular pathogenesis underlying EVI1-related leukemogenesis provides insight into how shared stemness transcriptional programs contribute to leukemia progression and therapeutic resistance in AML. Here, we review the current knowledge regarding the role of EVI1 in HSC self-renewal and leukemogenesis and highlight the relationship between stem cell self-renewal properties and adverse outcome in myeloid malignancies.

| S-EPMC7659387 | biostudies-literature

Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis.

Project description:The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.

| S-EPMC6773521 | biostudies-literature

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of CDK6 in MLL-rearranged myeloid leukemia.

Project description:Acute myeloid leukaemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukaemia (MLL) is an aggressive subtype with low overall survival. Bortezomib (Bort) is first applied in multiple myeloma. However, whether bort possesses anti-self-renewal and leukemogenesis of leukaemia stem cell (LSC) in AML with MLL rearrangements is still unclear. Here, we found that bort suppressed cell proliferation and decreased colony formation in human and murine leukaemic blasts. Besides, bort reduced the frequency and function of LSC, inhibited the progression, and extended the overall survival in MLL-AF9 (MF9) -transformed leukaemic mice. Furthermore, bort decreased the percentage of human LSC (CD34+ CD38- ) cells and extended the overall survival in AML blasts-xenografted NOD/SCID-IL2Rγ (NSG) mice. Mechanistically, cyclin dependent kinase 6 (CDK6) was identified as a bort target by RNA sequencing. Bort reduced the expressions of CDK6 by inhibiting NF ĸB recruitment to the promoter of CDK6, leading to the abolishment of NF ĸB DNA-binding activity for CDK6 promoter. Overexpression of CDK6 partially rescued bort-induced anti-leukemogenesis. Most importantly, bort had little side-effect against the normal haematological stem and progenitor cell (HSPC) and did not affect CDK6 expression in normal HSPC. In conclusion, our results suggest that bort selectively targets LSC in MLL rearrangements. Bort might be a prospective drug for AML patients bearing MLL rearrangements.

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METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism.

Project description:N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.

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