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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-06-1677.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3164-3173
NEOPLASIA
Suppression of myeloid transcription factors and induction of
STAT response genes by AML-specific Flt3 mutations
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, and
Hubert Serve
From the Department of Medicine, Hematology/Oncology,
University of Münster, Germany; the Department of
Hematology and Oncology, Osaka University Graduate School of Medicine,
Japan; and the Research Unit Molecular Cell Biology,
Medical Faculty, Friedrich Schiller University, Jena,
Germany.
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/EBP , 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.
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