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Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling.
- Source :
-
Blood [Blood] 2012 Jul 26; Vol. 120 (4), pp. 868-79. Date of Electronic Publication: 2012 May 21. - Publication Year :
- 2012
-
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.
- Subjects :
- 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
Humans
Immunoenzyme Techniques
Leukemia, Myeloid, Acute genetics
Mice
Molecular Sequence Data
Oncogene Proteins, Fusion genetics
Phosphatidylinositol 3-Kinases genetics
Proto-Oncogene Proteins c-akt genetics
RNA, Messenger genetics
RUNX1 Translocation Partner 1 Protein
Real-Time Polymerase Chain Reaction
Receptors, Thrombopoietin genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Survival Rate
Thrombopoietin genetics
Translocation, Genetic
Tumor Cells, Cultured
Core Binding Factor Alpha 2 Subunit metabolism
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Oncogene Proteins, Fusion metabolism
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Receptors, Thrombopoietin metabolism
Thrombopoietin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 120
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 22613795
- Full Text :
- https://doi.org/10.1182/blood-2012-03-414649