Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patientderived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199-induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL.Significance: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

“…Promising results have been reported in TCF3-PBX1 B-ALL [127] and in hypodiploid B-ALL [6,11], suggesting that Bcl2 inhibition could be a encouraging strategy also for the treatment of these B-ALL subtypes. In conclusion, all preclinical data on Bcl2 inhibition in ALL confirmed the therapeutic potential of Bcl2 inhibition for B-ALL patients.…”

“…A recent study showed that, in a B-ALL patient-derived xenograft (PDX) model, hypodiploid cells are sensitive to the B-cell lymphoma (Bcl) 2 inhibitor Venetoclax (ABT-199), suggesting that Bcl2 inhibition could be a promising strategy for the treatment of hypodiploid B-ALL [6,11].…”

Pediatric acute lymphoblastic leukemia

“…131 Preclinical studies have identified activities of venetoclax against high-risk leukemias such as ETP ALL, KMT2A-rearranged ALL, TCF3-HLF-positive ALL, and hypodiploid ALL (Table 2). 132,133 Proteasome and mTOR inhibitors have shown efficacy in relapsed ALL. 134,135 DOT1L, bromodomain, menin, and histone deacetylate inhibitors have shown promise in preclinical studies as therapies targeting unique molecular characteristics of KMT2A-rearranged ALL.…”

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia

“…Venetoclax plus chemotherapy is exhibiting good efficacy in adult refractory/relapsed T-ALL [159] . Additionally, preclinical studies have shown remarkable effectivity in childhood B-ALL [160] and the first phase I trials are currently developing, with encouraging results (NCT03181126) [161] .…”