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

Authors: 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.
Article Title: 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.
Keywords: cancer survival; controlled study; unclassified drug; acute granulocytic leukemia; human cell; gene deletion; nonhuman; cell proliferation; mouse; apoptosis; gene expression profiling; protein depletion; protein protein interaction; animal experiment; animal model; transcription factor; cell renewal; cell differentiation; rna binding protein; messenger rna; myc protein; leukemia cell; leukemogenesis; cancer stem cell; hematopoietic system; rna translation; loss of function mutation; correlational study; leukemia stem cell; nuclear reprogramming; genetic correlation; protein rna binding; colony formation; transcription factor hoxa9; mixed lineage leukemia protein; human; priority journal; article; murine leukemia; ikzf2 protein; rna binding protein musashi2
Journal Title: Journal of Clinical Investigation
Volume: 125
Issue: 3
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2015-03-03
Start Page: 1286
End Page: 1298
Language: English
DOI: 10.1172/jci78440
PROVIDER: scopus
PUBMED: 25664853
PMCID: PMC4362230
Notes: Export Date: 2 April 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Mithat Gonen
    824 Gonen
  2. Martin Stuart Tallman
    562 Tallman
  3. Ross Levine
    611 Levine
  4. Christina Leslie
    141 Leslie
  5. Ly P Vu
    31 Vu
  6. Patrick Edward Tivnan
    10 Tivnan
  7. Michael Kharas
    66 Kharas
  8. Sun Mi Park
    18 Park
  9. Yuheng Lu
    17 Lu
  10. Trevor Stephen Barlowe
    11 Barlowe
  11. James Christopher Taggart
    12 Taggart