Major finding: Genetic lesions associated with relapsed ALL converge on WNT and MAPK pathways.
Approach: Three high-throughput analyses were performed on bone marrow samples from patients with ALL.
Impact: Therapeutic strategies for relapsed ALL should target relapse-specific genetic events.
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, characterized by overproduction of immature malignant white blood cells in the bone marrow. Although the cure rate is relatively high, prognosis tends to be poor for relapses, which are often chemoresistant. To better characterize genetic changes associated with relapse, Hogan and colleagues analyzed gene expression, copy number abnormalities (CNA), and DNA methylation of matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL. Gene expression profiling revealed a different gene signature in patients with early versus late relapse, with genes involved in nucleotide biosynthesis and folate metabolism specifically up-regulated at late relapse. CNA analysis identified copy number changes mostly shared between diagnosis and relapse in the same patient, and DNA methylation showed a distinctly higher CpG methylation level at relapse versus diagnosis. To pinpoint a common relapse-driving genetic event, the authors then used cross-platform integration to compare all three genomic profiles. CDKN2A, CSMD1, PTPRO, and COL6A were significantly different between diagnosis and relapse in all three assays and have been found to be either epigenetically silenced or to act as tumor suppressors in multiple cancers, excluding COL6A. Further analysis revealed convergence of the genetic changes on the WNT/β-catenin and mitogen activated protein kinase (MAPK) signaling pathways, two biologically relevant pathways in cancer. Overall, the data forward our understanding of the key genetic events that drive the timing and occurrence of relapsed ALL, as well as inform the identification of novel therapeutic targets.
Hogan LE, Meyer JA, Yang J, Wang J, Wong N, Yang W, et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood. 2011 Sept 14. [Epub ahead of print]
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