Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.
RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).
Kharas
Michael G
MG
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. mkharas@partners.org
Lengner
Christopher J
CJ
Al-Shahrour
Fatima
F
Bullinger
Lars
L
Ball
Brian
B
Zaidi
Samir
S
Morgan
Kelly
K
Tam
Winnie
W
Paktinat
Mahnaz
M
Okabe
Rachel
R
Gozo
Maricel
M
Einhorn
William
W
Lane
Steven W
SW
Scholl
Claudia
C
Fröhling
Stefan
S
Fleming
Mark
M
Ebert
Benjamin L
BL
Gilliland
D Gary
DG
Jaenisch
Rudolf
R
Daley
George Q
GQ
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
D014408:Biomarkers, Tumor; C499059:Msi2h protein, mouse; D016601:RNA-Binding Proteins