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

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 i...

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Bibliographic Details
Published in:Blood 2006-10, Vol.108 (8), p.2764-2769
Main Authors: Pollard, Jessica A., Alonzo, Todd A., Gerbing, Robert B., Woods, William G., Lange, Beverly J., Sweetser, David A., Radich, Jerald P., Bernstein, Irwin D., Meshinchi, Soheil
Format: Article
Language:English
Subjects:
Alleles
Antigens, CD - metabolism
Antigens, CD34 - metabolism
Antigens, Differentiation, Myelomonocytic - metabolism
Child
Colony-Forming Units Assay
Erythroid Precursor Cells - enzymology
Erythroid Precursor Cells - immunology
fms-Like Tyrosine Kinase 3 - genetics
Hematopoietic Stem Cells - enzymology
Hematopoietic Stem Cells - immunology
Humans
In Vitro Techniques
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - immunology
Mutation
Neoplasia
Neoplastic Stem Cells - enzymology
Neoplastic Stem Cells - immunology
Prognosis
Sialic Acid Binding Ig-like Lectin 3
Tandem Repeat Sequences
Tumor Stem Cell Assay
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2006-04-012260