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Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

ABSTRACT: Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduced AML rate and extended survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibited AML cell survival, reduced leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. Combination of miRisten with chemotherapy further enhanced the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a new therapeutic approach for inv(16) AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE184015 | GEO | 2021/09/15

REPOSITORIES: GEO

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miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance

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2016-03-31 | PXD001994 | Pride

miR-126 governs human leukemia stem cell quiescence and therapeutic resistance

Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic regulation balances normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic modifiers are now considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly predictive of patient survival. Gain of function genetic analysis demonstrated that miR-126 restrained cell cycle progression, prevented LSC differentiation, and increased LSC self-renewal. miR-126 promoted chemo-resistance, preserving LSC quiescence in part through suppression of the G0 to G1 gatekeeper, CDK3. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC. 74 primary patient normal karyotype AML samples were analyzed for miRNA expression.

2016-02-01 | E-GEOD-55770 | biostudies-arrayexpress

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Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Project description:Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

| PRJNA762718 | ENA

Gene expression data from sorted and unsorted primary human acute myeloid leukemia (AML) samples

Project description:Experiments using xenografts show that some solid tumours and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSC). Despite promise, the relevance of the CSC model to human disease remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model based on sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSC) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSC and HSC, revealing the molecular machinery underlying stemness properties. Both stem cell programs were highly significant independent predictors of patient survival and also found in existing prognostic signatures. Thus, determinants of stemness influence clinical outcome of AML establishing that LSC are clinically relevant and not mere artifacts of xenotransplantation. Analysis of gene expression in FACS sorted AML fractions that were functionally determined to be enriched for LSC or not (25 and 29 respectively).

2011-08-27 | E-GEOD-30375 | biostudies-arrayexpress

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