Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling
Authors
Pulikkan, John A.Madera, Dmitri
Xue, Liting
Bradley, Paul
Landrette, Sean F.
Kuo, Ya-Huei
Abbas, Saman
Zhu, Lihua Julie
Valk, Peter J.
Castilla, Lucio H.
UMass Chan Affiliations
Program in Gene Function and ExpressionDocument Type
Journal ArticlePublication Date
2012-07-26Keywords
Leukemia, Myeloid, AcuteReceptors, Thrombopoietin
Core Binding Factor Alpha 2 Subunit
Genetics and Genomics
Hemic and Lymphatic Diseases
Metadata
Show full item recordAbstract
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.Source
Blood. 2012 Jul 26;120(4):868-79. Epub 2012 May 21. Link to article on publisher's siteDOI
10.1182/blood-2012-03-414649Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43983PubMed ID
22613795Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1182/blood-2012-03-414649