TY - JOUR
T1 - Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling
T2 - Correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome
AU - Harvey, Richard C.
AU - Mullighan, Charles G.
AU - Wang, Xuefei
AU - Dobbin, Kevin K.
AU - Davidson, George S.
AU - Bedrick, Edward J.
AU - Chen, I. Ming
AU - Atlas, Susan R.
AU - Kang, Huining
AU - Ar, Kerem
AU - Wilson, Carla S.
AU - Wharton, Walker
AU - Murphy, Maurice
AU - Devidas, Meenakshi
AU - Carroll, Andrew J.
AU - Borowitz, Michael J.
AU - Bowman, W. Paul
AU - Downing, James R.
AU - Relling, Mary
AU - Yang, Jun
AU - Bhojwani, Deepa
AU - Carroll, William L.
AU - Camitta, Bruce
AU - Reaman, Gregory H.
AU - Smith, Malcolm
AU - Hunger, Stephen P.
AU - Willman, Cheryl L.
PY - 2010/12/2
Y1 - 2010/12/2
N2 - 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 highrisk 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.
AB - 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 highrisk 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.
UR - http://www.scopus.com/inward/record.url?scp=78649742010&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-08-239681
DO - 10.1182/blood-2009-08-239681
M3 - Article
C2 - 20699438
AN - SCOPUS:78649742010
SN - 0006-4971
VL - 116
SP - 4874
EP - 4884
JO - Blood
JF - Blood
IS - 23
ER -