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FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation.
- Source :
-
Blood [Blood] 2009 Dec 03; Vol. 114 (24), pp. 5034-43. Date of Electronic Publication: 2009 Oct 06. - Publication Year :
- 2009
-
Abstract
- Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34(+)CD38(-) LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
- Subjects :
- Apoptosis drug effects
Blotting, Western
Cell Survival
Enzyme Activation physiology
Flow Cytometry
Humans
Leukemia, Myeloid, Acute metabolism
Myeloid Cell Leukemia Sequence 1 Protein
Polymerase Chain Reaction
Proto-Oncogene Proteins c-bcl-2 metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tandem Repeat Sequences
Up-Regulation
fms-Like Tyrosine Kinase 3 metabolism
Gene Expression Regulation, Neoplastic genetics
Leukemia, Myeloid, Acute genetics
Neoplastic Stem Cells metabolism
Proto-Oncogene Proteins c-bcl-2 genetics
STAT5 Transcription Factor metabolism
fms-Like Tyrosine Kinase 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 114
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 19808698
- Full Text :
- https://doi.org/10.1182/blood-2008-12-196055