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.

Integrated bioinformatics analysis of the crucial candidate genes and pathways associated with glucocorticoid resistance in acute lymphoblastic leukemia

“…Real et al proposed that upregulation of CCND2 is involved in the protection against Gamma‐secretase inhibitors (GSIs), which are Notch pathway inhibitors used in GC‐resistant T‐cell acute lymphoblastic leukemia (T‐ALL) . Additionally, reliability of the top enriched pathway associated with GC resistance, Transcriptional misregulation in cancer, is further supported by studies reporting that BCL2A1, PAX5, and CXCL8 play important roles in GC‐resistant ALL . Moreover, Pathways in cancer (map05200 on KEGG website) comprised various oncogenesis signaling pathways including MAPK, JAT/STAT, and PI3K‐AKT signaling pathways, which were confirmed to promote development of GC resistance in leukemia by multiple independent studies .…”

Up-regulated A20 promotes proliferation, regulates cell cycle progression and induces chemotherapy resistance of acute lymphoblastic leukemia cells

“…Although great improvements have been made in the treatment of pediatric leukemia, adult ALL remains a high burden [3]. This burden is partly due to uncontrolled cell proliferation and poor response to chemotherapy in adult patients [4]. Leukemic cells abnormally express numerous genes that are associated with proliferation and apoptosis compared to normal hematopoietic cells, and these genes are thought to be the main cause of drug resistance [5].…”

The pharmacogenomics of drug resistance to protein kinase inhibitors

“…PKIs induce upregulation and stabilization of BIM through inhibition of the MAPK pathway, therefore, the activity of BIM is required for PKIs to induce apoptosis in kinase-driven cancers (Gong et al, 2007). Recently, a 2,903 bp germline deletion polymorphism in intron 2 of BIM was identified, which was associated with inferior responses to PKIs (i.e., imatinib, gefitinib, erlotinib, and afatinib) in chronic myeloid leukemia (CML), non-small cell lung cancer (NSCLC), and pediatric ALL patients (Lee et al, 2014; Ng et al, 2012; Soh et al, 2014). Functionally, this mutation results in alternative RNA splicing, leading to decreased production of BIM isoforms containing the essential BH3 domain.…”