Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells.

Abstract

PURPOSE:

Activating length mutations in the juxtamembrane domain (FLT3-LM) and mutations in the tyrosine kinase domain (FLT3-TKD) of FLT3 represent the most frequent genetic alterations in acute myeloid leukemia (AML). However, the functional role of active FLT3 mutants in primary AML blast cells is not well characterized.

EXPERIMENTAL DESIGN:

We analyzed the transforming potential and the signaling of FLT3-ITD mutants in Ba/F3 cells and in primary AML blasts.

RESULTS:

FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. In contrast to the FLT3-ITD mutants, the ligand-stimulated FLT3-WT receptor was unable to transduce a fully proliferative response in Ba/F3 and monocytic OCI-AML5 cells. The ligand-stimulated FLT3-WT receptor activated AKT and MAPK, but not STAT5. In primary blast cells from 60 patients with AML, FLT3 was expressed in 91.9% of patients carrying a FLT3-LM/TKD mutation compared with 77.8% in FLT3-LM/TKD-negative patients. STAT3 and STAT5 were constitutively activated in 76 and 63% of patients, respectively. In accordance with the results in Ba/F3 cells, a high FLT3 expression and the presence of a FLT3-LM was strongly associated with the STAT5 but not with the STAT3 activation in primary AML blast cells. Moreover, the constitutive tyrosine phosphorylation of STAT5 was efficiently down-regulated by a FLT3 protein tyrosine kinase inhibitor in AML cells expressing an active FLT3 mutant.

CONCLUSIONS:

Active FLT3 receptor mutants have transforming potential in hematopoietic cells and induce a strong activation of STAT5 in primary AML cells. The FLT3-STAT5 pathway contributes to the malignant phenotype and represents a promising molecular therapeutic target structure in AML.

• Authors: Karsten Spiekermann, Ksenia Bagrintseva, Ruth Schwab, Karin Schmieja, Wolfgang Hiddemann
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 6 Pg. 2140-50 (Jun 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12796379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Indoles
• Milk Proteins
• Proto-Oncogene Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• STAT5 Transcription Factor
• SU 5614
• Trans-Activators
• FLT3 protein, human
• Receptor Protein-Tyrosine Kinases
• fms-Like Tyrosine Kinase 3
• Mitogen-Activated Protein Kinases

Topics

• Amino Acid Sequence
• Cell Transformation, Neoplastic
• DNA-Binding Proteins (physiology)
• Enzyme Activation
• Humans
• Indoles (pharmacology)
• Leukemia, Myeloid, Acute (metabolism, pathology, therapy)
• Milk Proteins
• Mitogen-Activated Protein Kinases (metabolism)
• Molecular Sequence Data
• Phosphorylation
• Proto-Oncogene Proteins (physiology)
• Receptor Protein-Tyrosine Kinases (physiology)
• STAT3 Transcription Factor
• STAT5 Transcription Factor
• Trans-Activators (physiology)
• fms-Like Tyrosine Kinase 3