title: Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia.
abstract: A broad range of anti-cancer agents, including glucocorticoids (GCs) and tyrosine kinase inhibitors (TKIs), kill cells by upregulating the pro-apoptotic BCL2 family member, BIM. A common germline deletion in the BIM gene was recently shown to favor the production of non-apoptotic BIM isoforms, and to predict inferior responses in TKI-treated chronic myeloid leukemia (CML) and EGFR-driven lung cancer patients. Given that both in vitro and in vivo GC resistance are predictive of adverse outcomes in acute lymphoblastic leukemia (ALL), we hypothesized that this polymorphism would mediate GC resistance, and serve as a biomarker of poor response in ALL. Accordingly, we used zinc finger nucleases to generate ALL cell lines with the BIM deletion, and confirmed the ability of the deletion to mediate GC resistance in vitro. In contrast to CML and lung cancer, the BIM deletion did not predict for poorer clinical outcome in a retrospective analysis of 411 pediatric ALL patients who were uniformly treated with GCs and chemotherapy. Underlying the lack of prognostic significance, we found that the chemotherapy agents used in our cohort (vincristine, L-asparaginase, and methotrexate) were each able to induce ALL cell death in a BIM-independent fashion, and resensitize BIM deletion-containing cells to GCs. Together, our work demonstrates how effective therapy can overcome intrinsic resistance in ALL patients, and suggests the potential of using combinations of drugs that work via divergent mechanisms of cell killing to surmount BIM deletion-mediated drug resistance in other cancers.
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Sheila Xinxuan
authors.initials: SX
authors.lastname: Soh
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Joshua Yew Suang
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: John W J
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore, Singapore; Viva-University Children's Cancer Centre, University Children's Medical Institute, National University Health System, Singapore, Singapore; Cancer Science Institute, National University of Singapore, Singapore, Singapore.
authors.forename: Allen Eng Juh
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of Haematology, Singapore General Hospital, Singapore, Singapore; Department of Medical Oncology, National Cancer Centre, Singapore, Singapore; Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone
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