Abstract:
:The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 x 10(-16)). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.
journal_name
Bloodjournal_title
Bloodauthors
Yang JJ,Bhojwani D,Yang W,Cai X,Stocco G,Crews K,Wang J,Morrison D,Devidas M,Hunger SP,Willman CL,Raetz EA,Pui CH,Evans WE,Relling MV,Carroll WLdoi
10.1182/blood-2008-06-165027subject
Has Abstractpub_date
2008-11-15 00:00:00pages
4178-83issue
10eissn
0006-4971issn
1528-0020pii
blood-2008-06-165027journal_volume
112pub_type
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