Avaliação de variantes do FLT3 em pacientes com leucemia mieloide aguda atendidos na Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas

Abstract

Acute myeloid leukemia (AML) is a disease heterogeneous hematological, which develops in the bone marrow after genetic and epigenetic changes in hematopoietic precursors, resulting in the clonal proliferation of blast cells of the myeloid lineage. Variations in the FMS-Like Tyrosine kinase 3 (FLT3) gene, as internal tandem duplication (FLT3-ITD) and variant in the D835 codon are reported frequently 30% and 10% of the cases, respectively. These mutations are associated with poor survival and risk of relapse. However, data on other variants in the FLT3 exome are not reported. Objective: This study aimed to evaluate variants in FLT3 in patients with AML treated at the Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas. Methodology: Were evaluated 36 patients diagnosed with AML of both genders and aged between 18-92. Bone marrow samples were collected and identification of FLT3 exome variants was performed by Sanger sequencing. Results: Different FLT3 gene variants were identified, total of 26 variants in 18 patients. Missense variants were found in functional domains, as 6 (23.1%) extracellular (EC), 3 (11.5%) transmembrane (TM), 1 (3.9%) juxtamembrane (JM), 5 (19.2%) in the tyrosine kinase I domain (TKD1) and 4 (15.4%) tyrosine kinase II domain (TKD2). FLT3-ITD variants were identified 3 (11.5%) in the JM domain and 4 in TKD1 (15.4%). The allele frequency (VAF) of pathogenic variants ranged from 11-62.5%. Missense variants were related with intense thrombocytopenia (p=0.038) and increased blasts in peripheral blood (p=0.014). Higher hemoglobin values were observed in patients with FLT3-ITD (p=0.049). The presence of a variant in the FLT3 gene can be identified in patients with secondary AML and in relapse, as discussed in a report of 4 cases, therefore the majority were identified in new AML (75%). Conclusion: This study highlights the occurrence of different potentially pathogenic variants in the FLT3 gene in patients with AML, the missense variants as most prevalent and related with hematological changes, highlighting the importance of screening variants in the FLT3 exome