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To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined risk group with few known recurring cytogenetic abnormalities and a poor outcome, we performed gene expression profiling (GEP) 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 GEP data revealed eight unique cluster groups within these high-risk ALL patients, two of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and six 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 a 4-year relapse-free survival (RFS) of 94.7+/-5.1%, compared to 63.5+/-3.7% for the cohort (P=0.01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, 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 RFS (21.0+/-9.5%; P<.001). These studies reveal the striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes which may serve as new targets for diagnosis, risk classification, and therapy.
The University of New Mexico Cancer Center and Departments of Pathology, Internal Medicine, Mathematics & Statistics, and Physics & Astronomy, University of New Mexico, Albuquerque, NM;
This article was published in the following journal.
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An organization of insurers or reinsurers through which particular types of risk are shared or pooled. The risk of high loss by a particular insurance company is transferred to the group as a whole (the insurance pool) with premiums, losses, and expenses shared in agreed amounts.
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