Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome.
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% ± 5.1%, compared with 63.5% ± 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% ± 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy.
Harvey
Richard C
RC
University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA.
Mullighan
Charles G
CG
Wang
Xuefei
X
Dobbin
Kevin K
KK
Davidson
George S
GS
Bedrick
Edward J
EJ
Chen
I-Ming
IM
Atlas
Susan R
SR
Kang
Huining
H
Ar
Kerem
K
Wilson
Carla S
CS
Wharton
Walker
W
Murphy
Maurice
M
Devidas
Meenakshi
M
Carroll
Andrew J
AJ
Borowitz
Michael J
MJ
Bowman
W Paul
WP
Downing
James R
JR
Relling
Mary
M
Yang
Jun
J
Bhojwani
Deepa
D
Carroll
William L
WL
Camitta
Bruce
B
Reaman
Gregory H
GH
Smith
Malcolm
M
Hunger
Stephen P
SP
Willman
Cheryl L
CL
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002986:Clinical Trials as Topic; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016896:Treatment Outcome
D014408:Biomarkers, Tumor