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

Blood. 2012 Jul 26;120(4):868-79. doi: 10.1182/blood-2012-03-414649. Epub 2012 May 21.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Bone Marrow Transplantation
  • Cell Cycle
  • Cell Proliferation
  • Chromosomes, Human, Pair 21 / genetics
  • Chromosomes, Human, Pair 8 / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology*
  • Mice
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • RUNX1 Translocation Partner 1 Protein
  • Real-Time Polymerase Chain Reaction
  • Receptors, Thrombopoietin / genetics
  • Receptors, Thrombopoietin / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survival Rate
  • Thrombopoietin / genetics
  • Thrombopoietin / metabolism*
  • Translocation, Genetic
  • Tumor Cells, Cultured

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • RNA, Messenger
  • RUNX1 Translocation Partner 1 Protein
  • Receptors, Thrombopoietin
  • MPL protein, human
  • Thrombopoietin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt