The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model.
Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two-megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL.
Mercher
Thomas
T
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Raffel
Glen D
GD
Moore
Sandra A
SA
Cornejo
Melanie G
MG
Baudry-Bluteau
Dominique
D
Cagnard
Nicolas
N
Jesneck
Jonathan L
JL
Pikman
Yana
Y
Cullen
Dana
D
Williams
Ifor R
IR
Akashi
Koichi
K
Shigematsu
Hirokazu
H
Bourquin
Jean-Pierre
JP
Giovannini
Marco
M
Vainchenker
William
W
Levine
Ross L
RL
Lee
Benjamin H
BH
Bernard
Olivier A
OA
Gilliland
D Gary
DG
D000818:Animals; D004195:Disease Models, Animal; D006410:Hematopoiesis; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C481270:Mpl protein, mouse; C532421:OTT-MAL fusion protein, human; D015514:Oncogene Proteins, Fusion; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D053628:Receptors, Thrombopoietin