title: 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.
abstract: 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.
authors.affiliation: University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Xuefei
authors.initials: X
authors.lastname: Wang
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Dobbin
authors.forename: George S
authors.initials: GS
authors.lastname: Davidson
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bedrick
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Susan R
authors.initials: SR
authors.lastname: Atlas
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Kerem
authors.initials: K
authors.lastname: Ar
authors.forename: Carla S
authors.initials: CS
authors.lastname: Wilson
authors.forename: Walker
authors.initials: W
authors.lastname: Wharton
authors.forename: Maurice
authors.initials: M
authors.lastname: Murphy
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Mary
authors.initials: M
authors.lastname: Relling
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Bruce
authors.initials: B
authors.lastname: Camitta
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
mesh_terms: 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
chemical_list: D014408:Biomarkers, Tumor