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 singlenucleotide 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 ؋ 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. (Blood. 2008;112: 4178-4183)
IntroductionOwing to advances in risk-adapted combination chemotherapy, the great majority of children with acute lymphoblastic leukemia (ALL) will survive beyond 5 years after initial presentation of leukemia. 1 However, 15% to 20% of ALL patients will have a relapse, making relapsed ALL the fifth most common childhood cancer in the United States. 2 Unlike newly diagnosed ALL, the prognosis of relapsed ALL is relatively poor, even with aggressive retrieval therapies. Five-year event-free survival of relapsed ALL is only 10% to 40%, depending on the length of first remission. 3 Consistent with clinical observations, Klumper et al have demonstrated that leukemia cells obtained at relapse were dramatically more resistant to many chemotherapeutic agents compared with cells from the initial tumor of the same person. 4 For example, the drug concentration of prednisone needed to kill 50% of leukemia cells (LC 50 ) increased by as much as 357-fold from diagnosis to relapse.Analyses of antigen receptor gene rearrangements indicate that, in almost all cases, the relapsed population of cells is clonally related to the original diagnostic sample. 5 Thus, whereas 50% of relapsed leukemia samples exhibit a novel clonal marker that was absent at diagnosis, 94% of relapse samples share at least one marker with the corresponding initial leukemia. Similar studies comparing genetic lesions between diagnosis and relapse provide evidence for the evolution or selection of the relapse leukemic clone. 6,7 Lesions specific to relapse are of particular importance because they constitute strong candidates responsible for drug resis...
