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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3907-3914
NEOPLASIA
Flt3 mutations from patients with acute myeloid leukemia induce
transformation of 32D cells mediated by the Ras and STAT5
pathways
Masao Mizuki,
Regina Fenski,
Hartmut Halfter,
Itaru Matsumura,
Rainer Schmidt,
Carsten Müller,
Wolfram Grüning,
Karsten Kratz-Albers,
Susanne Serve,
Claudia Steur,
Thomas Büchner,
Joachim Kienast,
Yuzuru Kanakura,
Wolfgang E. Berdel, and
Hubert Serve
From the Department of Medicine/Hematology and
Oncology, and the Department of Neurology, University of Münster,
Germany and the Department of Hematology and Oncology, Osaka University
Medical School, Japan.
Somatic mutations of the receptor tyrosine kinase Flt3 consisting
of internal tandem duplications (ITD) occur in 20% of patients with
acute myeloid leukemia. They are associated with a poor prognosis of
the disease. In this study, we characterized the oncogenic potential
and signaling properties of Flt3 mutations. We constructed chimeric
molecules that consisted of the murine Flt3 backbone and a 510-base
pair human Flt3 fragment, which contained either 4 different ITD
mutants or the wild-type coding sequence. Flt3 isoforms containing ITD
mutations (Flt3-ITD) induced factor-independent growth and resistance
to radiation-induced apoptosis in 32D cells. Cells containing
Flt3-ITD, but not those containing wild-type Flt3 (Flt3-WT), formed
colonies in methylcellulose. Injection of 32D/Flt3-ITD induced rapid
development of a leukemia-type disease in syngeneic mice. Flt3-ITD
mutations exhibited constitutive autophosphorylation of the immature
form of the Flt3 receptor. Analysis of the involved signal transduction
pathways revealed that Flt3-ITD only slightly activated the MAP kinases
Erk1 and 2 and the protein kinase B (Akt) in the absence of ligand and
retained ligand-induced activation of these enzymes. However, Flt3-ITD
led to strong factor-independent activation of STAT5. The relative
importance of the STAT5 and Ras pathways for ITD-induced colony
formation was assessed by transfection of dominant negative (dn)
forms of these proteins: transfection of dnSTAT5 inhibited colony
formation by 50%. Despite its weak constitutive activation by
Flt3-ITD, dnRas also strongly inhibited Flt3-ITD-mediated colony
formation. Taken together, Flt3-ITD mutations induce factor-independent
growth and leukemogenesis of 32D cells that are mediated by the Ras and
STAT5 pathways.
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