Blood Journal
Leading the way in experimental and clinical research in hematology

Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

  1. John Anto Pulikkan1,*,
  2. Dmitri Madera1,*,
  3. Liting Xue1,
  4. Paul Bradley1,
  5. Sean Francis Landrette1,
  6. Ya-Huei Kuo1,
  7. Saman Abbas2,
  8. Lihua Julie Zhu1,
  9. Peter Valk2, and
  10. Lucio Hernán Castilla1
  1. 1Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA; and
  2. 2Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands


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 up-regulation of Mpl expression in mice induces AML when coexpressed 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 up-regulation 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.

  • Submitted February 29, 2012.
  • Accepted May 15, 2012.
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