title: Analysis of FLT3-ITD and FLT3-Asp835 mutations in de novo acute myeloid leukemia: evaluation of incidence, distribution pattern, correlation with cytogenetics and characterization of internal tandem duplication from Indian population.
abstract: Mutation of the FMS-like tyrosine kinase 3 (FLT3) gene in Indian population remains unclear till date. Here, we found FLT3-ITD mutations in 19.1%, FLT3-Asp835 mutations in 4.7%, and dual mutations in 4.2%, accounting for overall mutation in 28% of acute myeloid leukemia (AML) patients. FLT3 mutation was more prevalent in APL than non-APL patients (32.2% vs 26.3%), adults tend to show higher incidence than children (30.6% vs 18.2%, p = .1), and were significantly associated with normal karyotype, high WBCs, with no specific distribution in FAB subtypes. Notably, FLT3 mutation was present in 50% of patients with NPM1-Mt, when compared to only 22.6% of patients with NPM1-wt (p < .001). Sequence analyses of internal tandem duplications (ITDs) revealed that duplications were mostly restricted to JM domain (3 to 165 nucleotides). Interestingly, 92.3% cases showed duplication of at least one amino acid (AA) within the stretch Y589 to K602 that includes the two SH2-binding motifs. Analysis of frequency of single AA in the duplicated region revealed that E598 was the most frequently duplicated single AA in 72%, followed by R595 (69.2%), and Y599 (66.7%). Finally, three types of point mutations were identified, including D835Y, D835H, and D835A.
authors.affiliation: Research and Development Division, Super Religare Laboratories Ltd (Formerly SRL Ranbaxy Ltd), Plot No.124, 17th Street, MIDC, Andheri (E), Mumbai, India.
authors.forename: Firoz
authors.initials: F
authors.lastname: Ahmad
authors.forename: Swarna
authors.initials: S
authors.lastname: Mandava
authors.forename: Bibhu Ranjan
authors.initials: BR
authors.lastname: Das
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D005787:Gene Frequency; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007194:India / Q000453:epidemiology; D007223:Infant; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D017354:Point Mutation; D020080:Tandem Repeat Sequences; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3