Regulation of myeloid leukaemia by the cell-fate determinant Musashi.
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.
Ito
Takahiro
T
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kwon
Hyog Young
HY
Zimdahl
Bryan
B
Congdon
Kendra L
KL
Blum
Jordan
J
Lento
William E
WE
Zhao
Chen
C
Lagoo
Anand
A
Gerrard
Gareth
G
Foroni
Letizia
L
Goldman
John
J
Goh
Harriet
H
Kim
Soo-Hyun
SH
Kim
Dong-Wook
DW
Chuah
Charles
C
Oehler
Vivian G
VG
Radich
Jerald P
JP
Jordan
Craig T
CT
Reya
Tannishtha
T
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
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