MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

Taggart, James; Ho, Tzu‐Chieh; Amin, Elianna; Xu, Huiling; Barlowe, Trevor; Perez, Almudena Chaves; Durham, Benjamin H.; Tivnan, Patrick; Okabe, Rachel; Chow, Arthur; Vu, Ly; Park, Sun Mi; Prieto, Camila; Famulare, Christopher; Patel, Minal; Lengner, Christopher J.; Verma, Amit; Roboz, Gail J.; Guzmán, Mónica L.; Klimek, Virginia M.; Abdel‐Wahab, Omar; Leslie, Christina; Nimer, Stephen D.; Kharas, Michael G.

doi:10.1038/ncomms10739

Cited by 27 publications

(26 citation statements)

References 26 publications

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“…MSI2 was for the first time linked to roles in supporting stem cell gene signatures and disease progression in myelodysplastic syndromes (MDS) (58). Overall, these and other studies have identified a large number of targets of Musashi-dependent expression, which besides those mentioned above include Hoxa9, Myc, Ikzf2 (53), NF-YA, a regulator of the proteasome (59), and Jagged1 (54).…”

Section: Demonstration Of Driver Roles For Musashi Expression In Oncomentioning

confidence: 99%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

208

240

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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as regulators of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers, glioblastoma, and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target.

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Section: Demonstration Of Driver Roles For Musashi Expression In Oncomentioning

confidence: 99%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

208

240

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“…The relevance and requirement of MSI2 function in leukemia was demonstrated by deletion or depletion of MSI2 with a germline gene-trap knockout or shRNAs resulting in reduced leukemogenesis in a CML-BC model 25,26 , whereas forced overexpression of MSI2 and BCR-ABL or NUP98-HOXA13 leads to a more aggressive form of CML 26 or myelodysplastic syndromes 28 , respectively. MSI2 is upregulated 10-fold as CML progresses to blast crisis state in patients and shRNA-mediated MSI2 silencing blocks propagation of both CML-BC and AML cell lines 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Minuesa

Albanese

Chow

et al. 2018

Preprint

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“…Furthermore, while Msi2 knockout mice exhibit a modest reduction in blood cells and about 50% reduction in hematopoietic stem and progenitor cells (HSPCs), depletion of MSI2 severely reduced the frequency and activity of LSCs in both mouse and human systems. This indicates a significantly higher dependency and requirement for MSI2 in LSCs and development of leukemia 20,[22][23][24][25][26] . The cause for this differential requirement for MSI2 function in LSCs and HSCs is not known.…”

mentioning

confidence: 99%

HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells

Nguyen

Chu

et al. 2020

Nat Commun

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The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2's oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.

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MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

Cited by 27 publications

References 26 publications

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells

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