Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program
Sun-Mi Park, … , Christopher J. Lengner, Michael G. Kharas
Sun-Mi Park, … , Christopher J. Lengner, Michael G. Kharas
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1286-1298. https://doi.org/10.1172/JCI78440.
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Research Article Oncology

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Abstract

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.

Authors

Sun-Mi Park, Mithat Gönen, Ly Vu, Gerard Minuesa, Patrick Tivnan, Trevor S. Barlowe, James Taggart, Yuheng Lu, Raquel P. Deering, Nir Hacohen, Maria E. Figueroa, Elisabeth Paietta, Hugo F. Fernandez, Martin S. Tallman, Ari Melnick, Ross Levine, Christina Leslie, Christopher J. Lengner, Michael G. Kharas

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Figure 1

MSI2-bound mRNAs are enriched for experimentally derived MLL transcriptional target genes.

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MSI2-bound mRNAs are enriched for experimentally derived MLL transcripti...
(A) GSEA plot shows MSI2 rank list of HITS-CLIP targets overlapping with MLL-AF9–controlled genes (FLAG-MSI2–bound mRNAs overlapped with indicated gene sets as performed in ref. 16). (B) GSEA plot with MLL-AF9 direct transcriptional chromatin immunoprecipitated targets, same as A. (C) GSEA of MLL-AF4 targets overlapped with HITS-CLIP targets same as in A. (D) MLL-AF9 primary leukemia cells were stained with indicated antibodies and gated. (E) Representative flow cytometric plot showing MSI2 intracellular staining in gating of c-Kithi and c-Kitlo cells. (F) Frequency of MSI2hi cells in c-Kithi and c-Kitlo population. Experiments (D–F) include samples from 2 independent transplants. n = 9 mice. Means and SEM, *P < 0.05., unpaired Student’s t test.