Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes.
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.
Lacayo
Norman J
NJ
Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Palo Alto, CA, USA.
Meshinchi
Soheil
S
Kinnunen
Paivi
P
Yu
Ron
R
Wang
Yan
Y
Stuber
Christianna M
CM
Douglas
Lorrie
L
Wahab
Romina
R
Becton
David L
DL
Weinstein
Howard
H
Chang
Myron N
MN
Willman
Cheryl L
CL
Radich
Jerald P
JP
Tibshirani
Robert
R
Ravindranath
Yaddanapudi
Y
Sikic
Branimir I
BI
Dahl
Gary V
GV
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D050677:Core Binding Factor Alpha 3 Subunit; D004265:DNA Helicases / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D018572:Disease-Free Survival; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D007951:Leukemia, Myeloid / Q000175:diagnosis* / Q000235:genetics; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000032:analysis; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis; D000075924:X-linked Nuclear Protein; D051941:fms-Like Tyrosine Kinase 3
D001549:Benzamides; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C493729:Runx3 protein, human; D014157:Transcription Factors; D000068877:Imatinib Mesylate; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein