Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study.
Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.
University of New Mexico Cancer Center and Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
Huining
H
Kang
Carla S
CS
Wilson
Richard C
RC
Harvey
I-Ming
IM
Chen
Maurice H
MH
Murphy
Susan R
SR
Atlas
Edward J
EJ
Bedrick
Meenakshi
M
Devidas
Andrew J
AJ
Carroll
Blaine W
BW
Robinson
Ronald W
RW
Stam
Maria G
MG
Valsecchi
Rob
R
Pieters
Nyla A
NA
Heerema
Joanne M
JM
Hilden
Carolyn A
CA
Felix
Gregory H
GH
Reaman
Bruce
B
Camitta
Naomi
N
Winick
William L
WL
Carroll
ZoAnn E
ZE
Dreyer
Stephen P
SP
Hunger
Cheryl L
CL
Willman
D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics; D016000:Cluster Analysis; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics; D035602:Transcriptional Elongation Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C501595:IRX2 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C410333:TACC2 protein, human; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3