Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia

• Published in: Science (American Association for the Advancement of Science) 2008-11, Vol.322 (5906), p.1377-1380
• Main Authors: Mullighan, Charles G., Phillips, Letha A., Su, Xiaoping, Ma, Jing, Miller, Christopher B., Shurtleff, Sheila A., Downing, James R.
• Format: Article
• Language: English
• Subjects: Acute T cell leukemia; B cell leukemia; B-Lymphocytes; Biological and medical sciences; Blood; Cell cycle; Cell Cycle - genetics; Cellular biology; Child; Cyclin-Dependent Kinase Inhibitor p15 - genetics; ETS Translocation Variant 6 Protein; Evolution; Gene Deletion; Gene Dosage; Genes; Genes, p16; Genome, Human; Genomics; Hematologic and hematopoietic diseases; Humans; Lesions; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Lymphopoiesis; Medical prognosis; Medical sciences; Metabolic Networks and Pathways - genetics; Mutation; Oligonucleotide Array Sequence Analysis; Pediatrics; Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-ets - genetics; Recurrence; Relapse; Repressor Proteins - genetics
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1164266

Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 pediatric patients with ALL. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs), with the CNAs acquired at relapse preferentially affecting genes implicated in cell cycle regulation and B cell development. Most relapse samples lacked some of the CNAs present at diagnosis, which suggests that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies revealed that cells corresponding to the relapse clone were often present as minor subpopulations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment, and they point to new targets for therapeutic intervention.