Life Science Journal 2012;9(4) http://www.lifesciencesite.com 1053 FLT3 internal tandem duplication and JAK2 V617F mutations in de novo acute myelogenous leukemia: relation with induction chemotherapy and overall survival Magda M Assem 1 , Magda M Noshy 2 , Ghada M Elsayed 1 , Hanan R Nassar 3 Gamal Thabet 1 , Ghada M Sherif 4 and Aida K Ahmad 2 1 Clinical Pathology and Oncologic Laboratory Medicine, National Cancer institute, Cairo University, Egypt 2 Zoology Department, Faculty of Science, Cairo University, Egypt 3 Medical oncology, National Cancer Institute, Cairo University, Egypt 4 Biostatistics and Epidemiology Department, National Cancer institute, Cairo University, Egypt elsayed276@yahoo.com; magda_assem123@yahoo.com Abstract: Molecular characterization of acute myeloid leukemia (AML) allows prognostic stratification and assessment of the chances of durable treatment response. The presence of FLT3 internal tandem duplication (ITD) mutation as well as the allelic ratio (ITD-AR) and JAK2 V617F mutation may be associated with clinical outcome in patients with AML. FLT3-ITD and JAK2 V617F mutation status was determined for 194 patients with de novo AML. ITD-AR was calculated for patients with FLT3- ITD. Clinical characteristics and outcomes for patients with different FLT3 genotypes were compared. In the total group of 194 patients, FLT3- ITD mutation was detected in 34 (17.5%) patients, 30 (18.8%) adults and 4 (11.8%) pediatric. JAK2-V617F mutation was detected in one patient (0.5%). Among the adult group, patients with FLT3/ITD had a significantly elevated diagnostic white blood cell count (WBC) compared to patients with FLT3 WT/WT genotype (p=0.02).Sixty three (61.2%) achieved complete remission (CR), 52 (82.5 %) were of the FLT3 WT/WT genotype and 11(17.5%) of the FLT3 WT/ITD genotype (p=0.75). Overall survival (OS) of patients with FLT3 WT/ITD group was shorter (28.5%) when compared with for the FLT3 WT/WT group (40.8%) although no significant difference was detected(p=0.2). The disease free survival (DFS) for patients with FLT3 WT/ITD genotype was (100%) compared to (86%) for patients with FLT3 WT/WT genotype, with no significant difference (p=0.3) between the two groups. In conclusion we found that FLT3-ITD mutation is a frequent finding in adult patients with de novo AML. There is a significant association between FLT3- ITD mutation with high WBC count and a tendency towards a worse prognosis. The ratio of mutant to wild allele level may have a strong relation to the patient outcome. JAK2-V617F mutation is infrequent finding in de novo AML. [Magda M Assem, Magda M Noshy, Ghada M Elsayed, Hanan R Nassar, Gamal Thabet, Ghada M Sherif and Aida K Ahmad. FLT3 internal tandem duplication and JAK2 V617F mutations in de novo acute myelogenous leukemia: relation with induction chemotherapy and overall survival. Life Sci J 2012;9(4):1053-1060]. (ISSN: 1097-8135). http://www.lifesciencesite.com . 160 Key words: AML, FLT3-ITD, JAK2 V617F 1. Introduction Acute myeloid leukemia is being revealed as an increasingly heterogeneous entity as the molecular aberrations underlying it are defined. Such information is fundamental in assessment of the chances of durable treatment response. Morphological complete remission is now achieved in the majority of patients with current chemotherapeutic regimens, so the main determinants of prognosis are therefore those variables that influence treatment-related death or relapse risk (1) . The Fms-like tyrosine kinase 3 (FLT3) genes encodes a class III tyrosine kinas that plays important roles in cellular proliferation and differentiation. To date, 2 types of FLT3 mutations have been found to induce autophosphorylation through ligand- independent FLT3 dimerization, leading to uncontrolled hematologic progenitor cell proliferation and malignancy. One such mutation is an internal tandem duplication of the region between exon 14 and 15 encoding the juxtamembrane domain; the other, in exon 20, is a point mutation in aspartic acid residue 835 (D835) within the activation loop of the second tyrosine kinase domain (2) . FLT3-ITD mutation is a common finding in approximately 25% of younger adult AML patients. Many studies have found that FLT3-ITD mutation is associated with adverse prognosis (3) . An acquired mutation in the JAK2 gene has recently been described in human myeloproliferative disorders (MPD). JAK2 is a cytoplasmic tyrosine kinase that plays an essential role in the signaling pathways of cytokines and growth factors. The mutation 1849 G>T, which leads to amino acid substitution of phenylalanine for a highly conserved valine (V617F), renders JAK2 kinase constitutively active and leads to cell proliferation in the absence of the growth factors (4) . Now there is evidence in the