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Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia

ABSTRACT: RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).

ORGANISM(S): Homo sapiens

PROVIDER: GSE16432 | GEO | 2010/07/11

SECONDARY ACCESSION(S): PRJNA129033

REPOSITORIES: GEO

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Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia

Project description:RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.

2010-07-11 | E-GEOD-16432 | biostudies-arrayexpress

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines)

Project description:We demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSC), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of Msi2 in a mouse model increases HSC cell cycle progression and cooperates with BCR-ABL1 to induce an aggressive leukemia. MSI2 is over-expressed in human myeloid leukemia, and expression levels directly correlate with decreased patient survival, thereby defining MSI2 expression as a novel prognostic marker in acute myeloid leukemia (AML). Depletion of MSI2 in human myeloid leukemia cells leads to decreased proliferation and apoptosis. These data implicate the MSI2 RNA binding protein in myeloid leukemogenesis and identify a novel potential target for therapy in AML. We transduced four human leukemia cell lines with lentiviral shRNA vectors targeting MSI2. Hybridizations of treated and control samples from each cell line were dye swap replicated

2010-07-21 | E-GEOD-22775 | biostudies-arrayexpress

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible)

Project description:We demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSC), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of Msi2 in a mouse model increases HSC cell cycle progression and cooperates with BCR-ABL1 to induce an aggressive leukemia. MSI2 is over-expressed in human myeloid leukemia, and expression levels directly correlate with decreased patient survival, thereby defining MSI2 expression as a novel prognostic marker in acute myeloid leukemia (AML). Depletion of MSI2 in human myeloid leukemia cells leads to decreased proliferation and apoptosis. These data implicate the MSI2 RNA binding protein in myeloid leukemogenesis and identify a novel potential target for therapy in AML. Hematopoietic stem cells and progenitor cells (LineageLow, Sca1-, Kit+; LK) from control and transgenic MSI2-inducible mice were isolated and RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction. cDNA was fragmented and biotinylated before hybridization onto Affymetrix Mouse Expression Array 430 2.0.

2010-07-21 | E-GEOD-22773 | biostudies-arrayexpress

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK)

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Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (Leukemia cell lines)

2010-07-21 | GSE22775 | GEO

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LK and MS12-inducible)

2010-07-21 | GSE22773 | GEO

Musashi 2 regulates normal hematopoiesis and accelerates leukemogenesis (LSK and LK)

Project description:We demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSC), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of Msi2 in a mouse model increases HSC cell cycle progression and cooperates with BCR-ABL1 to induce an aggressive leukemia. MSI2 is over-expressed in human myeloid leukemia, and expression levels directly correlate with decreased patient survival, thereby defining MSI2 expression as a novel prognostic marker in acute myeloid leukemia (AML). Depletion of MSI2 in human myeloid leukemia cells leads to decreased proliferation and apoptosis. These data implicate the MSI2 RNA binding protein in myeloid leukemogenesis and identify a novel potential target for therapy in AML. Mouse hematopoietic stem cells (defined as LineageLow, Sca1+, Kit+; LSK; n=3) as well as committed progenitor cells (LineageLow, Sca1-, Kit+; LK; n=3) were sorted and RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction. cDNA was fragmented and biotinylated before hybridization onto Affymetrix Mouse Expression Array 430 2.0.

2010-07-22 | E-GEOD-22774 | biostudies-arrayexpress

Musashi 2 is a regulator of the hematopoietic stem cell compartment identified by a retroviral insertion screen and knockout mice

Project description:We have used a retroviral integration screen to search for novel genes that regulate hematopoietic stem cell (HSC) function. One of the genes that conferred HSC dominance when overexpressed due to an adjacent retroviral insertion was Musashi 2 (Msi2), an RNA binding protein that can act as a translational inhibitor. A gene trap mouse model that inactivates the gene shows that Msi2 is more highly expressed in long term (LT) and short term (ST) HSCs as well as in lymphoid myeloid primed progenitors (LMPPs), but much less in intermediate progenitors and mature cells. Mice lacking Msi2 are fully viable up to more than a year but exhibit severe defects in primitive precursors, most significantly a reduction in the number of ST-HSCs and LMPPs and a decrease of leukocyte numbers, effects that are exacerbated with age. Cell cycle and gene expression analyses suggest that the main hematopoietic defect in Msi2 defective mice consists in a decreased proliferation capacity of ST-HSCs and LMPPs. In addition, HSCs lacking Msi2 are severely impaired in competitive repopulation experiments, being overgrown by wild type cells even when mutant cells were provided in excess. Our data indicate that Msi2 maintains the stem cell compartment mainly by regulating the proliferation of primitive progenitors downstream of LT-HSCs. RNA from 2 different cell populations (LSK cells and KIT+ cells) were analyzed for both wildtype and Msi2-/- null samples. Two technical replicates were analyzed for the KIT+ samples and three technical replicates were analyzed for the LSK samples.

2011-05-21 | E-GEOD-29432 | biostudies-arrayexpress

Musashi-2 HITS-CLIP sequencing in K562 cells

Project description:Hematopoietic stem cells (HSCs) are maintained through the regulation of symmetric and asymmetric cell division. We report that conditional ablation of the RNA-binding protein Msi2 results in a failure of HSC maintenance and engraftment caused by a loss of quiescence and increased commitment divisions. Contrary to previous studies, we found that these phenotypes were independent of Numb. Global transcriptome profiling and RNA target analysis uncovered Msi2 interactions at multiple nodes within pathways that govern RNA translation, stem cell function, and TGF-β-signaling. Msi2-null HSCs are insensitive to TGF-β–mediated expansion and have decreased signaling output, resulting in a loss of myeloid-restricted HSCs and myeloid reconstitution. Thus, Msi2 is an important regulator of the HSC translatome and balances HSC homeostasis and lineage bias. One empty vector control– and two Flag-MSI2–overexpressing K562 cell samples were analyzed using HITS-CLIP protocol

2014-10-07 | E-GEOD-62115 | biostudies-arrayexpress

Musashi 2 is a regulator of the hematopoietic stem cell compartment identified by a retroviral insertion screen and knockout mice

2011-05-21 | GSE29432 | GEO

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