Blood, 1 November 2004, Vol. 104, No. 9, pp. 2646-2654.
Prepublished online as a Blood First Edition Paper on July 13, 2004; DOI 10.1182/blood-2003-12-4449.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes
Norman J. Lacayo,
Soheil Meshinchi,
Paivi Kinnunen,
Ron Yu,
Yan Wang,
Christianna M. Stuber,
Lorrie Douglas,
Romina Wahab,
David L. Becton,
Howard Weinstein,
Myron N. Chang,
Cheryl L. Willman,
Jerald P. Radich,
Robert Tibshirani,
Yaddanapudi Ravindranath,
Branimir I. Sikic, and
Gary V. Dahl
From the Divisions of Pediatric Hematology/Oncology, Medical Oncology, and Statistics, Stanford University School of Medicine, Palo Alto, CA; Arkansas Children's Hospital, Little Rock, AR; Massachusetts General Hospital, Boston, MA; the Children's Hospital of Michigan, Detroit, MI; the Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA; and the Children's Oncology Group, Arcadia, CA.
Fms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients. (Blood. 2004;104:2646-2654)
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