Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines

Abstract

In this study, we examined a large number of patients to clarify FLT3 gene has some structural similarities including the the distribution and frequency of a recently described FLT3 tannumber of exons, size of exons and exon/intron boundaries dem duplication among hematopoietic malignancies, including with genes RTKs, FMS, KIT, and platelet-derived growth-factor of 24 showed internal tandem duplication with or withoutWe recently demonstrated internal tandem duplication insertion of nucleotides. In one AML, insertion and deletion within JM/TK-I domains as a somatic mutation of FLT3 found without duplication was determined. All 24 lengthened in 17% of patients with acute myelogenous leukemia (AML). 14 sequences were in-frame. Duplication takes place in the Since this mutation was not found in any patients with acute sequence coding for the JM domain and leaves the TK domain lymphocytic leukemia, we described that this mutation could intact. In conclusion, we emphasize that the length mutation of FLT3 at JM/TK-I domains were restricted to AML and MDS.be specific in myeloid malignancies. To clarify the incidence Since all these mutations resulted in in-frame, this abnormality and distribution of the FLT3 mutation among hematological might function for the proliferation of leukemic cells.malignancies, we examined a large number of patients with

Detection of FLT3 Internal Tandem Duplication and D835 Mutations by a Multiplex Polymerase Chain Reaction and Capillary Electrophoresis Assay

“…10 FLT3 ITD mutations have been reported to occur in 20 to 30% of patients with AML and have been associated with an increased relapse risk, decreased disease-free survival, decreased event-free survival, and decreased overall survival. 8,9,11 In a multivariate analysis of FLT3 ITD mutations, cytogenetic risk group, presentation white blood cell count, percentage BM blasts at diagnosis, age, gender, and FAB type in 854 AML patients, the presence of a FLT3 ITD mutation was the most significant factor adversely affecting relapse risk (P Ͻ 0.0001) and disease-free survival (P Ͻ 0.0001). 9 FLT3 ITD mutations are amenable to polymerase chain reaction (PCR)-based molecular diagnostic DNA testing because they are limited to a small, predictable region of the FLT3 gene.…”

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy

“…[1][2][3] Mutations of the FLT3 gene have been reported in 25% of adult acute myeloid leukemia (AML), in 3-15% of myelodysplastic syndrome (MDS), and occasionally in chronic myeloid leukemia and lymphoproliferative disorders. [4][5][6][7] Usually, the mutated gene presents an internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence, which frequently involves exon 14 and more rarely intron 14 or exon 15,5,8 according to the recently description of the FLT3 locus by Abu-Duhier et al 9 Duplicated sequences of the JM domains have variable lengths but can always be read inframe. The role of FLT3-ITDs in leukemogenesis is still unclear.…”

Concepts of human leukemic development

“…Activating mutations in Flt-3 include internal tandem duplication of the juxtamembrane domain and the D835 point mutation in the activation loop. These have been identified in 17-34% and 7-10% of AML, respectively (Nakao et al, 1996;Yokota et al, 1997;Abu-Duhier et al, 2001;Yamamoto et al, 2001;Zheng et al, 2004). An additional 50% of AML samples express high levels of wild-type Flt-3 (Birg et al, 1992;Carow et al, 1996), and Flt-3 ligand (FL) induces proliferation of AML cells in vitro (Dehmel et al, 1996;Drexler et al, 1999).…”