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
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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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 6

Ikzf2 contributes to the survival of myeloid leukemia cells.

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Ikzf2 contributes to the survival of myeloid leukemia cells. (A) Median...
(A) Median fluorescence intensity of IKZF2 in the c-Kithi and c-Kitlo MLL-AF9 leukemic cells (n = 7, combined from 2 independent experiments). (B) Representative flow cytometric plot for intracellular staining of IKZF2 showing knockdown in c-Kithi cells derived from Msi2fl/fl leukemia cells transduced with scramble and 2 Ikzf2 shRNAs (1 and 2) from 3 experiments. (C) Colony formation assay of MLL-AF9 leukemic cells transduced with scramble or Ikzf2 shRNAs, same as in B, plated in methylcellulose and counted after 5 days; n = 5. (D) Proliferation at 6 days post-transduction; n = 4. (E) Apoptosis at 6 days post-transduction; n = 4. (F) Quantitative PCR of MLL-related genes in MLL-AF9 leukemic cells transduced with scramble or Ikzf2 shRNAs. Results are means and SEM of n = 4 for scramble and Ikzf2 shRNA2 and n = 3 for Ikzf2 shRNA1. *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test for A to F.