title: 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 fluorescence-activated 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 colony-forming 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.
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, D2-373, 1100 Fairview Ave N, Seattle, WA 98109, USA. jpollard@fhcrc.org
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Pollard
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: William G
authors.initials: WG
authors.lastname: Woods
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lange
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000483:Alleles; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002648:Child; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000201:enzymology / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000276:immunology; D011379:Prognosis; D063268:Sialic Acid Binding Ig-like Lectin 3; D020080:Tandem Repeat Sequences; D014410:Tumor Stem Cell Assay; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3