TY - JOUR
T1 - The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model
AU - Mercher, Thomas
AU - Raffel, Glen D.
AU - Moore, Sandra A.
AU - Cornejo, Melanie G.
AU - Baudry-Bluteau, Dominique
AU - Cagnard, Nicolas
AU - Jesneck, Jonathan L.
AU - Pikman, Yana
AU - Cullen, Dana
AU - Williams, Ifor R.
AU - Akashi, Koichi
AU - Shigematsu, Hirokazu
AU - Bourquin, Jean Pierre
AU - Giovannini, Marco
AU - Vainchenker, William
AU - Levine, Ross L.
AU - Lee, Benjamin H.
AU - Bernard, Olivier A.
AU - Gilliland, D. Gary
PY - 2009/4/1
Y1 - 2009/4/1
N2 - 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 κ 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.
AB - 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 κ 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.
UR - http://www.scopus.com/inward/record.url?scp=65249094196&partnerID=8YFLogxK
U2 - 10.1172/JCI35901
DO - 10.1172/JCI35901
M3 - Article
C2 - 19287095
AN - SCOPUS:65249094196
SN - 0021-9738
VL - 119
SP - 852
EP - 864
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -