Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The receptor tyrosine kinase Flt3 is expressed and functionally important in early myeloid progenitor cells and in the majority of acute myeloid leukemia (AML) blasts. Internal tandem duplications (ITDs) in the juxtamembrane domain of the receptor occur in 25% of AML cases. Previously, we have shown that these mutations activate the receptor and induce leukemic transformation. In this study, we performed genome-wide parallel expression analyses of 32Dcl3 cells stably transfected with either wild-type or 3 different ITD isoforms of Flt3. Comparison of microarray expression analyses revealed that 767 of 6586 genes differed in expression between FLT3-WT– and FLT3-ITD–expressing cell lines. The target genes of mutationally activated Flt3 resembled more closely those of the interleukin 3 (IL-3) receptor than those of ligand-activated Flt3. The serine-threonine kinase Pim-2 was up-regulated on the mRNA and the protein level in Flt3-ITD–expressing cells. Further experiments indicated that Pim-2 function was important for clonal growth of 32D cells. Several genes repressed by the mutations were found to be involved in myeloid gene regulation. Pu.1 and C/EBPα, both induced by ligand-activation of wild-type Flt3, were suppressed in their expression and function by the Flt3 mutations. In conclusion, internal tandem duplication mutations of Flt3 activate transcriptional programs that partially mimic IL-3 activity. Interestingly, other parts of the transcriptional program involve novel, IL-3–independent pathways that antagonize differentiation-inducing effects of wild-type Flt3. The identification of the transcriptional program induced by ITD mutations should ease the development of specific therapies.
Date Issued
2003-04-15
Date Acceptance
2002-11-23
Citation
Blood, 2003, 101 (8), pp.3164-3173
ISSN
0006-4971
Publisher
American Society of Hematology
Start Page
3164
End Page
3173
Journal / Book Title
Blood
Volume
101
Issue
8
Copyright Statement
"This research was originally published in Blood. Masao Mizuki, Joachim Schwäble, Claudia Steur, Chunaram Choudhary, Shuchi Agrawal, Bülent Sargin, Björn Steffen, Itaru Matsumura, Yuzuru Kanakura, Frank D. Böhmer, Carsten Müller-Tidow, Wolfgang E. Berdel, Hubert Serve; Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 2003; 101 (8): 3164–3173. doi: https://doi.org/10.1182/blood-2002-06-1677 © the American Society of Hematology."
Identifier
10.1182/blood-2002-06-1677
Publication Status
Published
Date Publish Online
2003-04-15