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.
authors: Sun-Mi
authors: SM
authors: Park
authors: Mithat
authors: M
authors: Gönen
authors: Ly
authors: L
authors: Vu
authors: Gerard
authors: G
authors: Minuesa
authors: Patrick
authors: P
authors: Tivnan
authors: Trevor S
authors: TS
authors: Barlowe
authors: James
authors: J
authors: Taggart
authors: Yuheng
authors: Y
authors: Lu
authors: Raquel P
authors: RP
authors: Deering
authors: Nir
authors: N
authors: Hacohen
authors: Maria E
authors: ME
authors: Figueroa
authors: Elisabeth
authors: E
authors: Paietta
authors: Hugo F
authors: HF
authors: Fernandez
authors: Martin S
authors: MS
authors: Tallman
authors: Ari
authors: A
authors: Melnick
authors: Ross
authors: R
authors: Levine
authors: Christina
authors: C
authors: Leslie
authors: Christopher J
authors: CJ
authors: Lengner
authors: Michael G
authors: MG
authors: Kharas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000502:physiology*; D059467:Transcriptome
chemical_list: C438151:MSI2 protein, human; D016601:RNA-Binding Proteins