Title
Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling
UMMS Affiliation
Program in Gene Function and Expression
Date
7-26-2012
Document Type
Article
Medical Subject Headings
Leukemia, Myeloid, Acute; Receptors, Thrombopoietin; Core Binding Factor Alpha 2 Subunit
Disciplines
Genetics and Genomics | Hemic and Lymphatic Diseases
Abstract
Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that upregulation of Mpl expression in mice induces AML when co-expressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that upregulation of wild type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.
Rights and Permissions
Citation: Blood. 2012 Jul 26;120(4):868-79. Epub 2012 May 21. Link to article on publisher's site