MiR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55917 | GEO | 2016/02/02
SECONDARY ACCESSION(S): PRJNA241307
REPOSITORIES: GEO
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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 mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are 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 human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.
2016-03-31 | PXD001994 | Pride
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
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.
2016-02-01 | GSE55770 | GEO
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 mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are 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 human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.
2016-02-02 | GSE55916 | GEO
Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSCs) 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.
2016-02-02 | GSE55814 | GEO
Project description:miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance
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Project description: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 reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances 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 therapeutic approach for inv(16) AML.
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Project description:Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.
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