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

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

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1286-1298
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number3
DOIs
StatePublished - Mar 2 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Park, S. M., Gönen, M., Vu, L., Minuesa, G., Tivnan, P., Barlowe, T. S., Taggart, J., Lu, Y., Deering, R. P., Hacohen, N., Figueroa, M. E., Paietta, E., Fernandez, H. F., Tallman, M. S., Melnick, A., Levine, R., Leslie, C., Lengner, C. J., & Kharas, M. G. (2015). Musashi2 sustains the mixed-lineage leukemia'driven stem cell regulatory program. Journal of Clinical Investigation, 125(3), 1286-1298. https://doi.org/10.1172/JCI78440