Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling
AuthorsPulikkan, John A.
Landrette, Sean F.
Zhu, Lihua Julie
Valk, Peter J.
Castilla, Lucio H.
UMass Chan AffiliationsProgram in Gene Function and Expression
Document TypeJournal Article
KeywordsLeukemia, Myeloid, Acute
Core Binding Factor Alpha 2 Subunit
Genetics and Genomics
Hemic and Lymphatic Diseases
MetadataShow full item record
AbstractOncogenic 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.
SourceBlood. 2012 Jul 26;120(4):868-79. Epub 2012 May 21. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/43983
Related ResourcesLink to Article in PubMed