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 2

Msi2 is required for efficient MLL leukemogenesis.

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Msi2 is required for efficient MLL leukemogenesis. (A) Experimental sch...
(A) Experimental scheme for LSK-derived MLL-AF9 initiation leukemia transplantation model. (B) Survival analysis of experiment scheme shown in A from indicated genotypes, n = 22 Msi2fl/fl and n = 19 Msi2Δ/Δ mice combined from 3 independent transplants. ****P < 0.0001, log-rank test. (C) White blood cell counts (WBCs) at 60 days post-transplantation as schemed in A were taken from n = 5 mice of each genotype. (D) Spleen weights at day 60 of indicated animals in C. Means and SEM, *P < 0.05, ***P < 0.005, unpaired Student’s t test. (E) Representative micrograph of indicated spleens from mice at 60 days post-transplantation. (F) H&E staining of spleen and liver sections from moribund leukemic mice (representative image from 3 independent animals). Original magnification, ×100. Scale bars: 20 μm. (G) Experimental scheme for GMP-derived MLL-AF9 leukemia transplantation model. (H) Survival analysis combined from 4 independent experiments with indicated genotypes, n = 24 Msi2fl/fl and n = 25 Msi2Δ/Δ, is shown. **P < 0.01, log-rank test. Msi2Δ/Δ mice identified as not deleted were censored from the analysis (Supplemental Table 2 and Supplemental Figure 2, G and I). (I) Experimental scheme for the Msi2 MLL-AF9 maintenance leukemia transplantation model. (J) Survival analysis of data combined from 3 independent maintenance transplants with indicated genotypes, n = 28 Msi2fl/fl and n = 29 Msi2Δ/Δ. ***P < 0.001, log-rank test. Unexcised Msi2 mice were censored from the survival curves (Supplemental Table 2 and Supplemental Figure 2, G and J).