Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling
Program in Gene Function and Expression
Leukemia, Myeloid, Acute; Receptors, Thrombopoietin; Core Binding Factor Alpha 2 Subunit
Genetics and Genomics | Hemic and Lymphatic Diseases
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.
DOI of Published Version
Blood. 2012 Jul 26;120(4):868-79. Epub 2012 May 21. Link to article on publisher's site
Pulikkan, John A.; Madera, Dmitri; Xue, Liting; Bradley, Paul; Landrette, Sean F.; Kuo, Ya-Huei; Abbas, Saman; Zhu, Lihua Julie; Valk, Peter J.; and Castilla, Lucio H., "Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling" (2012). Program in Gene Function and Expression Publications and Presentations. 193.