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Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential

ABSTRACT: Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential

PROVIDER: PRJNA305517 | ENA |

REPOSITORIES: ENA

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Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [RNA-seq]

Project description:microRNA are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify one such microRNA, miR-196b, is essential for MLL-AF9 leukemia initiation and maintenance. To discover how miR-196b contributes to leukemogenesis, we utilized multiple unbiased approaches that identified and functionally screened miR-196b target activity in AML. Our studies resolved how conflicting networks of miRNA-regulated targets are integrated during leukemogenesis. This work uncovered two miR-196b direct targets, the cell cycle regulator Cdkn1b (p27Kip1) and Polycomb group member Phc2, that independently cooperate with MLL-AF9 to promote leukemogenesis by regulating stem cell transcriptional programs. Finally, we found that therapeutic disruption of miR-196b direct targeting of Cdkn1b suppresses leukemogenesis.

2018-06-29 | GSE75842 | GEO

Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [Gene 1.0 ST]

2018-06-29 | GSE75841 | GEO

Rictor Plays a Pivotal Role in Maintaining Quiescence as well as Stemness of Leukemia Stem Cells in MLL-Driven Leukemia

Project description:Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of AML. Here, we demonstrated that Rictor is essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs. To understand the critical molecular events caused by Rictor loss in MLL-AF9-driven leukemia,the K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MA9_R1,MA9_R2,MA9_R3) or control(MA9_C1,MA9_C2,MA9_C3), and subjected to microarray analysis on Affymetrix microarrays.Furthermore, the MLL-NRIP3-driven mice model was chosen for further examination.The K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MN3_R1,MN3_R2,MN3_R3) or control(MN3_C1,MN3_C2,MN3_C3), and subjected to microarray analysis on Affymetrix microarrays.

2016-07-19 | E-GEOD-84505 | biostudies-arrayexpress

Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-06-28 | GSE75843 | GEO

Rictor Plays a Pivotal Role in Maintaining Quiescence as well as Stemness of Leukemia Stem Cells in MLL-Driven Leukemia

2016-07-19 | GSE84505 | GEO

Mus musculus

Project description:Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [RNA-seq]

| PRJNA305519 | ENA

LAMP5-AS1 drives leukemia cell stemness in MLL leukemia

Project description:LAMP5-AS1 drives leukemia cell stemness in MLL leukemia

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Project description:Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [Gene 1.0 ST]

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Sphingosine-1 phosphate receptor 1 (S1PR1) is crucial for maintaining the stem cell properties of acute myeloid leukemia stem cells

Project description:To identify the most important gene(s) for maintaining the stem cell properties of leukemia stem cells (LSCs), we analyzed the transcriptional profiles of LSC and non-LSC subsets from acute leukemia patients and identified S1PR1 as a novel biomarker of LSCs. Then to understand the underlying mechanisms of S1PR1-dependent stemness maintenance, we performed gene expression profiling analyses comparing CD34+S1PR1+ and CD34+S1PR1- cell fractions from AML patients and healthy donors; we also determined the global transcriptional response of KG1 cells to an inhibitor of S1PR1 (FTY720) at two concentrations.

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