TitleMusashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program.
Publication TypeJournal Article
Year of Publication2015
AuthorsPark, Sun-Mi, Gönen Mithat, Vu Ly, Minuesa Gerard, Tivnan Patrick, Barlowe Trevor S., Taggart James, Lu Yuheng, Deering Raquel P., Hacohen Nir, Figueroa Maria E., Paietta Elisabeth, Fernandez Hugo F., Tallman Martin S., Melnick Ari, Levine Ross, Leslie Christina, Lengner Christopher J., and Kharas Michael G.
JournalJ Clin Invest
Volume125
Issue3
Pagination1286-98
Date Published2015 Mar 02
ISSN1558-8238
KeywordsAnimals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Leukemic, Humans, Leukemia, Myeloid, Mice, Inbred C57BL, Mice, Transgenic, Neoplastic Stem Cells, Protein Binding, RNA-Binding Proteins, Transcriptome
Abstract

<p>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. </p>

DOI10.1172/JCI78440
Alternate JournalJ Clin Invest
PubMed ID25664853
PubMed Central IDPMC4362230
Grant ListU24-CA114737 / CA / NCI NIH HHS / United States
U10-CA180827 / CA / NCI NIH HHS / United States
U10 CA180801 / CA / NCI NIH HHS / United States
R01 CA16865 / CA / NCI NIH HHS / United States
R01-DK101989-01A1 / DK / NIDDK NIH HHS / United States
K01DK084261-01 / DK / NIDDK NIH HHS / United States
CA180801 / CA / NCI NIH HHS / United States
R01 CA193842 / CA / NCI NIH HHS / United States
CA180794 / CA / NCI NIH HHS / United States
U10 CA180820 / CA / NCI NIH HHS / United States
U24 CA114737 / CA / NCI NIH HHS / United States
CA180791 / CA / NCI NIH HHS / United States
U10 CA180827 / CA / NCI NIH HHS / United States
U10 CA021115 / CA / NCI NIH HHS / United States
UG1 CA189859 / CA / NCI NIH HHS / United States
CA180820 / CA / NCI NIH HHS / United States
U24 CA196172 / CA / NCI NIH HHS / United States
R01 DK101989 / DK / NIDDK NIH HHS / United States
K01 DK084261 / DK / NIDDK NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U10 CA180791 / CA / NCI NIH HHS / United States
CA189859 / CA / NCI NIH HHS / United States
U10 CA180794 / CA / NCI NIH HHS / United States