FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a clonal disease characterized by heterogeneous involvement of hematopoietic stem cell/ progenitor cell populations. Using FLT3 internal tandem duplication (FLT3/ITD) as a molecular marker, we tested the hypothesis that clinical outcome in AML correlates with disease involvement of CD34 / CD33 precursors. Diagnostic specimens from 24 children with FLT3/ITD-positive AML were sorted by fluorescenceactivated cell sorting (FACS), and resultant CD34 /CD33 and CD34 /CD33 progenitors were analyzed directly and after colony-forming cell (CFC) assay for the presence of FLT3/ITD. FLT3/ITD was present in all CD34 /CD33 patient samples. In contrast, FLT3/ITD was detected in CD34 /CD33 progenitors in only 19 of 24 samples. A bipotent progenitor was affected in a subset of patients, as evidenced by the presence of FLT3/ITD in both granulocyte-macrophage colonyforming unit (CFU-GM) and erythroid burst-forming unit (BFU-E) colonies. Those patients in whom CD34 /CD33 precursors harbored the FLT3/ITD had worse clinical outcome; actuarial event-free survival (EFS) at 4 years from study entry for those patients with and without FLT3/ITD detection in CD34 /CD33 progenitors was 11% 14% versus 100% 0%, respectively (P .002). This study suggests that FLT3/ITD involvement in CD34 /CD33 precursors is heterogeneous and that detection of the mutation in the less-mature progenitor population may be associated with disease resistance. (Blood.