title: Regulation of myeloid leukaemia by the cell-fate determinant Musashi.
abstract: Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ito
authors.forename: Hyog Young
authors.initials: HY
authors.lastname: Kwon
authors.forename: Bryan
authors.initials: B
authors.lastname: Zimdahl
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Congdon
authors.forename: Jordan
authors.initials: J
authors.lastname: Blum
authors.forename: William E
authors.initials: WE
authors.lastname: Lento
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Anand
authors.initials: A
authors.lastname: Lagoo
authors.forename: Gareth
authors.initials: G
authors.lastname: Gerrard
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: John
authors.initials: J
authors.lastname: Goldman
authors.forename: Harriet
authors.initials: H
authors.lastname: Goh
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Tannishtha
authors.initials: T
authors.lastname: Reya
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C438151:MSI2 protein, human; D008565:Membrane Proteins; C499059:Msi2h protein, mouse; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; D028861:Nuclear Pore Complex Proteins; C106293:Numb protein, mouse; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; C097899:homeobox protein HOXA9; C093350:nuclear pore complex protein 98; D016044:Fusion Proteins, bcr-abl