Multi-agent chemotherapy overcomes glucocorticoid resistance conferred by a BIM deletion polymorphism in pediatric acute lymphoblastic leukemia.

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

Methotrexate, vincristine, and L-asparaginase activate apoptosis in a BIM-independent manner, and overcome <i>BIM</i> deletion-mediated GC resistance.

<p>CCRF-CEM clones were treated with dexamethasone (DEX) (0.1 µM) with or without (<b>A</b>) methotrexate (MTX) (1 µM), (<b>B</b>) vincristine (VCR) (2 ng/ml), or (C) L-asparaginase (ASP) (0.5 IU/ml) for 48 h. Following incubation, cell lysates were obtained and analyzed for cleaved PARP and caspase 3, as well as BIM induction. β-actin was used as a loading control.</p

Retrospective analysis of the Ma-Spore ALL 2003 cohort according to the presence or absence of the <i>BIM</i> deletion polymorphism.

<p>Kaplan-Meier curves comparing event-free survival (<b>A</b>) or overall survival (<b>B</b>) in patients with or without the <i>BIM</i> deletion polymorphism are shown.</p

Biological and clinical features of patients from the Ma-Spore ALL 2003 trial genotyped for the <i>BIM</i> polymorphism.

<p>Incidence of the <i>BIM</i> polymorphism is 50 out of 411 patients, or 12.2%. Abbreviations: Ma-Spore, Malaysia- Singapore; MRD, minimal residual disease; NCI, National Cancer Institute; PCR, polymerase chain reaction; CCR, continuous complete remission.</p>∧<p>indicates that data was unavailable for some patients.</p

Pediatric non–Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4–15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number o

Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse

Recent genomic profiling of childhood acute lymphoblastic leukemia (ALL) identified a novel high-risk subtype with a gene expression signature resembling Philadelphia chromosome-positive ALL and a poor prognosis (Ph-like ALL). However, the role of inherited genetic variation in Ph-like ALL pathogenesis remains unknown. In a genome-wide association study (GWAS) of 511 ALL cases and 6,661 non-ALL controls, we identified a single susceptibility locus for Ph-like ALL (GATA3, rs3824662, P=2.17×10(−14), odds ratio [OR]=3.85, for Ph-like ALL vs. non-ALL; P=1.05×10(−8), OR=3.25, for Ph-like ALL vs. non-Ph-like ALL) that was independently validated. The rs3824662 risk allele was associated with somatic lesions underlying Ph-like ALL (i.e., CRLF2 rearrangement, JAK mutation, and IKZF1 deletion) and directly influenced GATA3 transcription. Finally, GATA3 SNP genotype was also associated with early treatment response and the risk of ALL relapse. Our results provide insights into interactions between host and tumor genomes and their importance in ALL pathogenesis and prognosis