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

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

PROVIDER: PRJNA762718 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15864327.fastq.gz	Fastqsanger.gz
	SRR15864328.fastq.gz	Fastqsanger.gz
	SRR15864329.fastq.gz	Fastqsanger.gz
	SRR15864330.fastq.gz	Fastqsanger.gz
	SRR15864331.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

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 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.

2021-09-15 | GSE184015 | GEO

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

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.

| S-EPMC8536759 | biostudies-literature

The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling

Project description:Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion CBF::MYH11 oncoprotein regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBF::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBF::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

2024-11-18 | GSE215613 | GEO

Mouse inv(16):TET2ko granulocyte macrophage progenitor (GMP) cells

Project description:inv(16)/Tet2-/- GMPs (Lin- Sca1- ckit+ CD41- FcgR+ CD150-) were FACS sorted as described in Supplementary Information (Reckzeh, K et al 2020) TET2 deficiency cooperates with CBFB-MYH11 to induce acute myeloid leukemia and represents an early leukemogenic event. Reckzeh, K et al.

2022-03-28 | GSE161390 | GEO

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

Transcriptome Sequence Analysis of Pediatric Acute Megakaryoblastic Leukemia Identifies An Inv(16)(p13.3;q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein As a Recurrent Lesion in 39% of Non-Infant Cases

Project description:This SuperSeries is composed of the following subset Series: GSE35201: Transcriptome Sequence Analysis of Pediatric Acute Megakaryoblastic Leukemia Identifies An Inv(16)(p13.3;q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein As a Recurrent Lesion in 39% of Non-Infant Cases [2007] GSE35202: Transcriptome Sequence Analysis of Pediatric Acute Megakaryoblastic Leukemia Identifies An Inv(16)(p13.3;q24.3)-Encoded CBFA2T3-GLIS2 Fusion Protein As a Recurrent Lesion in 39% of Non-Infant Cases [2010] Refer to individual Series

2012-11-20 | E-GEOD-35203 | biostudies-arrayexpress

Vibrio cholerae strain:V-126-16 | isolate:V-126-16

Project description:Vibrio cholerae strain:V-126-16 | isolate:V-126-16 Genome sequencing and assembly

| PRJNA378296 | ENA

inv(16)/t(16;16) acute myeloid leukemia with non-type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

Project description:The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and KIT mutation status between type A (n=182; 87%) and non-type A (n=26; 13%) patients. We derived a fusion-type-associated gene- global expression profile. Gene Ontology analysis of the differentially expressed genes revealed - among others - an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients.

2013-01-23 | E-MTAB-1356 | biostudies-arrayexpress

Both gain and loss of function of miR-126 promote t(8;21) leukemia progression with different consequences and through different mechanisms

Project description:To investigate the pathological effect of miR-126 on the progression of acute myeloid leukemia (AML) induced by AML1-ETO9a (AE9a), we conducted a series of mouse bone marrow transplantation (BMT) assays with the following groups: AE9a (primary donor cells were wild-type mouse bone marrow progenitor (i.e., lineage negative; Lin-) cells retrovirally transduced with MSCV-PIG-AE9a), AE9a+miR-126 (primary donor cells were wild-type mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG-AE9a-miR-126), and miR-126KO+AE9a (primary donor cells were miR-126 knockout mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG-AE9a), along with a control group (primary donor cells were wild-type mouse bone marrow progenitor (i.e., Lin-) cells retrovirally transduced with MSCV-PIG empty vector). The control group was only used in the primary and secondary BMT assays, whereas the three leukemic groups including AE9a, AE9a+miR-126 and miR-126KO+AE9a were used in four passages (i.e., primary, secondary, tertiary and quaternary) of BMT assays. Then, gene expression profiling was conducted with bone marrow samples collected from different groups to decipher the molecular mechanisms underlying miR-126 effects on leukemia initiation and progression and maintenance and self-renewal of leukemia stem/initiating cells.

2015-09-07 | GSE65939 | GEO

Genome wide N-MYC binding in human inv(16) AML cells

Project description:To identify the role of N-MYC in transcriptional regulation in human inv(16) AML, we conducted conducted CUT&Tag analysis for N-MYC and H3K27AC in ME-1 cells

2023-10-17 | GSE227930 | GEO

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