A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study

Abstract

SUMMARY Background In childhood acute lymphoblastic leukemia (ALL) genetic subtypes are recognized that determine the risk-group for further treatment. However, 25% of precursor BALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. Methods A classifier based on gene expression in ALL cells from 190 newly diagnosed pediatric cases was constructed using a double-loop cross-validation method and next, was validated on an independent cohort of 107 newly diagnosed pediatric ALL cases. Hierarchical cluster analysis using classifying gene probe sets then revealed a novel ALL subtype for which underlying genetic abnormalities were characterized by comparative genomic hybridization-arrays and molecular cytogenetics. Findings The prediction accuracy of the classifier was median 90% in the discovery cohort and 87.9% in the independent validation cohort. A significant part of the currently genetically unclassified cases clustered with BCR-ABL-positive cases in both the discovery and validation cohort. These BCR-ABL-like cases represent 15–20% of ALL cases and have a highly unfavorable outcome (5-year disease-free survival 59.5%, 95%CI: 37.1%–81.9%) compared to other precursor B-ALL cases (84.4%, 95%CI: 76.8%–92.1%; P=0.012), similar to the poor prognosis of BCR-ABL-positive ALL (51.9%, 95%CI: 23.1%–80.6%), as was confirmed in the validation cohort. Further genetic studies revealed that the BCR-ABL-like subtype is characterized by a high frequency of deletions in genes involved in B-cell development (82%), including IKAROS, E2A, EBF1, PAX5 and VPREB1, compared to other ALL cases (36%, p=0.0002). BCR-ABL-like leukemic cells were median >70-times resistant to L-asparaginase (p=0.001) and 1.6-times more resistant to daunorubicin (p=0.017) compared to other precursor B-ALL cases whereas the toxicity of prednisolone and vincristine did not significantly differ. Interpretation Classification by gene expression profiling identified a novel subtype of ALL not detected by current diagnostic procedures but which comprises the largest group of patients with a high-risk of treatment failure. New treatment strategies are needed to improve outcome for this novel high-risk subtype of ALL. Funding Dutch Cancer Society, Sophia Foundation for Medical Research, Pediatric Oncology Foundation Rotterdam, Center of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute and American Lebanese Syrian Associated Charities.