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

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 nonmutant 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. Leukemia (2000) 14, 675-683.

How to Establish Acute Myeloid Leukemia Xenograft Models Using Immunodeficient Mice

“…Additionally, NOD/SCID mice were both insulitis-and diabetes-free throughout life . Subsequent transplant of NOD/SCID mice resulted in appreciably higher engraftment rates using fewer cells (Dick, 1996a;Bonnet and Dick, 1997), with ensuing xenografts preserving observed morphological, phenotypical, genotypical and biological characteristics of the donors AML cells (Dick, 1996b;Blair et al, 1998;Ailles et al, 1999;Rombouts et al, 2000a;Lumkul et al, 2002;Marx, 2003). Cells from patients with poor prognostic markers (e.g.…”

“…Cells from patients with poor prognostic markers (e.g. high WBC, poor risk cytogenetics, FLT3-ITD positive, high CD34 expression) engrafted more efficiently in NOD/SCID mice than general AML cases (Ailles et al, 1999;Kondo et al, 1999;Rombouts et al, 2000a;Rombouts et al, 2000b;Lumkul et al, 2002;Pearce et al, 2006). However, there was a report showed that high WBC and FLT3-ITD were not predictors of engraftment success (Pearce et al, 2006).…”

Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

“…1 Recent screens have also identified a range of other point mutations in FLT3 in AML. [2][3][4] FLT3-ITD and FLT3-TKD mutants induce distinct disease states in mouse models 5 and although FLT3-ITD mutations are associated with a poor prognosis, [6][7][8][9] the prognostic implications of FLT3-TKD mutations are less clear. 9,10 The signaling events induced by the activated FLT3 mutants presumably converge to modulate gene expression changes contributing to survival, proliferation and maintenance of differentiation arrest.…”

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

“…Although, FLT-3 is expressed in leukemias of both lymphoid and myeloid lineage (28), the development of small-molecule FLT-3 inhibitors was driven by the predominance of FLT-3 mutations in AML and their association with a poor prognosis for both adult (29) and pediatric patients (30,31). Results from experiments involving inhibitor, SU11657, in this study provided evidence of a relationship between FLT-3 activation and VEGF secretion.…”