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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55770 | GEO | 2016/02/01

SECONDARY ACCESSION(S): PRJNA240981

REPOSITORIES: GEO

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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 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

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

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

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.

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

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2008-06-12 | E-GEOD-3725 | biostudies-arrayexpress

Transcription profiling of human HSC enriched population, common myeloid progenitors, granulocyte macrophage progenitors, megakaryocyte progenitors, and leukemia stem cells (leukemic-GMP) reveals MLL-AF9 transforms committed progenitors to leukemia stem cells by activation of a stem cell program (expt 2)

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2008-06-12 | E-GEOD-3722 | biostudies-arrayexpress

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2022-08-10 | GSE157702 | GEO

Transcription profiling of isolated granulocyte macrophage progenitors were incubated with a retrovirus that expressed either GFP or MLL-AF9 and GFP reveals MLL-AF9 transforms committed progenitors to leukemia stem cells by activation of a stem cell program (expt 1)

Project description:Leukemias and other cancers possess a rare population of cells capable of self-renewal, and eradication of these cancer stem cells is likely necessary for long-term cancer-free survival. Given that both normal and cancer stem cells are capable of self-renewal the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. We introduced the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23) found in human acute myelogenous leukemia (AML) into murine committed granulocyte-macrophage progenitors (GMP). The resultant leukemias contained cells with an immunophenotype similar to normal GMP that were highly enriched for leukemia stem cells (LSC). Detailed gene expression comparisons between normal hematopoietic stem cells (HSC), committed progenitors, and the LSC population demonstrated the LSC were globally more similar to the normal GMP than any other population. However, a subset of genes highly expressed in normal stem cells was re-activated in the LSC. These data demonstrate LSC can be generated from committed progenitors without widespread reprogramming of gene expression, and a leukemia self-renewal associated signature is activated in the process. Our findings define progression from normal hematopoietic progenitor to leukemia stem cell, and suggest that targeting a self-renewal program expressed in an abnormal context may be possible. Experiment Overall Design: isolated granulocyte macrophage progenitors were incubated with a retrovirus that expressed either GFP or MLL-AF9 and GFP. Forty hours later, the GFP positive cells were isolated and RNA was hybrided to Affymetrix microarrays. The experiment was repeated three times.

2008-06-12 | E-GEOD-3721 | biostudies-arrayexpress

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2015-01-15 | E-GEOD-64545 | biostudies-arrayexpress

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