The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model

被引：85

作者：

Mercher, Thomas ^{[2
]}

Raffel, Glen D. ^{[2
]}

Moore, Sandra A. ^{[2
]}

Cornejo, Melanie G. ^{[2
]}

Baudry-Bluteau, Dominique

Cagnard, Nicolas

Jesneck, Jonathan L. ^{[3
]}

Pikman, Yana ^{[2
]}

Cullen, Dana ^{[2
]}

Williams, Ifor R. ^{[4
]}

Akashi, Koichi ^{[3
]}

Shigematsu, Hirokazu ^{[3
]}

Bourquin, Jean-Pierre ^{[5
]}

Giovannini, Marco ^{[6
]}

Vainchenker, William ^{[7
]}

Levine, Ross L. ^{[2
]}

Lee, Benjamin H. ^{[2
]}

Bernard, Olivier A. ^{[1
]}

Gilliland, D. Gary ^{[2
,8
]}

机构：

[1] Tour Pasteur Hop Necker, INSERM, EM10210, F-75743 Paris 15, France

[2] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Hematol,Med Sch, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA

[5] Univ Zurich, Childrens Hosp, Dept Oncol, Zurich, Switzerland

[6] Fdn Jean Dausset CEPH, INSERM, U674, Paris, France

[7] Univ Paris 11, Inst Gustave Roussy, INSERM, U790, Villejuif, France

[8] Howard Hughes Med Inst, Cambridge, MA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 04期

关键词：

MEGAKARYOCYTE DEVELOPMENT; GATA3; EXPRESSION; NOTCH; THROMBOPOIETIN; MUTATIONS; BIOLOGY; GENE; DIFFERENTIATION; PATHWAY; IDENTIFICATION;

D O I：

10.1172/JCI35901

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Acute megakaryoblastic leukemia (AMKL) is a font 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 K 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.

引用

页码：852 / 864

页数：13

共 55 条

[31] Notch signaling specifies megakaryocyte development from hematopoietic stem cells [J].