Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene

Publisher Website
Google Scholar
Abstract
Internal tandem duplications of the Flt3 gene (Flt3/ITDs) are present in about 18% of all AML cases and are therefore one of the most frequent somatic gene mutations in AML. Little is known about the role of Flt3/ITDs in leukemogenesis or their clinical relevance. In this study we compared 18 samples with Flt3/ITDs and 63 AML samples without these mutations with respect to clinical prognosis, cytokine responsiveness, progenitor cell content and repopulation in the NOD/SCID mouse. We found that in patients with a mutation CR rates are reduced (P = 0.03) and relapse rates are increased (P = 0.01), indicating the prognostic importance of Flt3/ITDs. This is also emphasized by the finding that in patients under the age of 60 years, as well as in older patients the event-free survival was more unfavorable for the mutant patients (P = 0.003 and P = 0.03, respectively). At diagnosis Flt3/ITD and non-mutant AML bone marrow samples did not differ in their progenitor/stem cell frequencies. Cobblestone area forming cell (CAFC) subsets showed a similar frequency distribution in mutant and non-mutant samples. In 7-day liquid cultures, Flt3/ITD samples showed a reduced growth in response to a variety of myeloid growth factors. In contrast, Flt3/ITD samples displayed a higher ability to engraft the NOD/SCID bone marrow with leukemic cells. Together these data show that the Flt3/ITD represents an important diagnostic marker for patient prognosis, and that the presence of these mutations is associated with altered proliferative ability of progenitors in vivo and in vitro.