TY - JOUR
T1 - Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes
AU - Lacayo, Norman J.
AU - Meshinchi, Soheil
AU - Kinnunen, Paivi
AU - Yu, Ron
AU - Wang, Yan
AU - Stuber, Christianna M.
AU - Douglas, Lorrie
AU - Wahab, Romina
AU - Becton, David L.
AU - Weinstein, Howard
AU - Chang, Myron N.
AU - Willman, Cheryl L.
AU - Radich, Jerald P.
AU - Tibshirani, Robert
AU - Ravindranath, Yaddanapudi
AU - Sikic, Branimir I.
AU - Dahl, Gary V.
PY - 2004/11/1
Y1 - 2004/11/1
N2 - Fms-like tyrosine kinase 3 (FLT3) initiations 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 ihe 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.
AB - Fms-like tyrosine kinase 3 (FLT3) initiations 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 ihe 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.
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U2 - 10.1182/blood-2003-12-4449
DO - 10.1182/blood-2003-12-4449
M3 - Article
C2 - 15251987
AN - SCOPUS:7244236503
SN - 0006-4971
VL - 104
SP - 2646
EP - 2654
JO - Blood
JF - Blood
IS - 9
ER -