Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia

Abstract

IntroductionThe prevalence and significance of several genetic abnormalities in patients with acute myeloid leukemia (AML) have been reported. The most powerful prognostic factor in AML has been the karyotype of the leukemia cells. 1 Three cytogenetic risk groups (favorable, intermediate, and poor) are widely accepted, but there is a practical limitation to the definition of cytogenetic risk, especially in patients falling in the intermediate group. Additional prognostic factors are therefore required. It has been reported that abnormalities in the RAS and p53 genes as well as the FLT3 gene are implicated in the pathogenesis of AML. [2][3][4][5][6][7] Mutations in FLT3, RAS, and p53 have been found in approximately 30%, 20%, and 5% to 10% of adult AML cases, respectively, indicating that mutations in these 3 genes are the most frequent genetic alterations in AML.We and several groups have demonstrated that FLT3 mutations are a strong prognostic factor in AML. [8][9][10][11][12][13][14][15][16][17][18] To date, several large-scale analyses have revealed that FLT3 mutations are essentially found in myeloid-lineage leukemia cells. 16,19,20 However, FLT3 mutations within an activation-loop were found in 5 of 30 acute lymphoblastic leukemia (ALL) cases with mixed-lineage leukemia (MLL) gene-rearranged ALL. 21 It is notable that FLT3 was highly expressed in MLL gene-rearranged ALL, leading to the constitutive activation of wild-type FLT3 kinase, and that primary ALL cells and an ALL cell line SEMK2-M1, which strongly expressed FLT3 but did not carry FLT3 mutations, had the same sensitivity to a potent FLT3 inhibitor as leukemia cells and a cell line with FLT3 mutations. 21,22 FLT3 is preferentially expressed on hematopoietic stem cells as well as in the brain, placenta, and liver. 23,24 The ligand to FLT3 (FL) is expressed as a membrane-bound or soluble form by bone marrow stroma cells and stimulates the stem cells alone or in cooperation with other cytokines. 25-32 FL-FLT3 interaction, therefore, plays an important role in the survival, proliferation, and differentiation of stem cells. In FLT3-expressing leukemia cells, FL stimulation enhances proliferation and reduces apoptosis.Although FLT3 is expressed on the surface of a high proportion of AML cells as well as B-lineage ALL cells, [33][34][35][36][37] little is known about the clinical significance of the FLT3 expression level in acute leukemia. In this study, we analyzed the expression level of the FLT3 transcript quantitatively in comparison with several gene alterations in 181 de novo AML cases. Because the prevalence of the MLL gene rearrangement is lower in adult de novo AML than in therapy-related AML and in infant or childhood acute leukemia, the From the Department of Infectious Diseases and the Department of Hematology, Nagoya University School of Medicine, Japan; the Department of Medicine, Japanese Red Cross Nagoya First Hospital; the Department of Medicine, Saiseikai Maebashi Hospital, Japan; the Research and Development Center for Higher Education, N...

Hox genes in hematopoiesis and leukemogenesis

“…This hypothesis is corroborated by the finding that MEIS1 upregulates the pro-proliferative and pro-survival receptor tyrosine kinase Flt3 in Hoxa9 and NUP98-HOX models of leukemia, indicating that Flt3 is a major downstream effector of the leukemic collaboration between Hox and Meis1 (Wang et al, 2005Palmqvist et al, 2006). Consistent with this, elevated wild-type FLT3 levels are frequently observed in AML samples and correlate with elevated expression of HOX and MEIS1 (Ozeki et al, 2004;Quentmeier et al, 2004).…”

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

“…38 Overexpression of FLT3 also has been detected in acute myeloid leukemia patients without FLT3 mutations and it is associated with a poor overall survival. 39 These data argue that patients with FLT3 mutations may require their own therapeutic regimens, including FLT3 inhibitors, agents that target the aberrantly activated FLT3 kinase. In fact, FLT3 inhibitors have attracted broad attention as new therapeutic agents for acute myeloid leukemia, and there are multiple clinical trials that are currently in progress.…”

Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT

“…Our analysis is, however, limited by the absence of data on expression of novel molecular prognostic markers of AML such as nucleophosmin-1 (NPM1) mutation, or allelic burden of FMS-related tyrosine kinase-3 (FLT-3) internal tandem duplication mutation and CCAAT/enhancer binding protein-α (CEBPA), among others. [40][41][42][43][44][45] This limitation is inherent to retrospective registry studies. Our findings shall provide the basis for a prospective randomized trial to confirm the results of this study.…”