Cotargeting BCL-2 and MCL-1 in high-risk B-ALL
Open Access
- 22 June 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (12), 2762-2767
- https://doi.org/10.1182/bloodadvances.2019001416
Abstract
Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph− and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.This publication has 24 references indexed in Scilit:
- Faculty Opinions recommendation of MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.Published by H1 Connect ,2015
- MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199Cell Reports, 2015
- New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemiaCancer, 2015
- Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemiaBlood, 2013
- Structure-guided design of a selective BCL-XL inhibitorNature Chemical Biology, 2013
- ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNature Medicine, 2013
- Case SeriesToxicologic Pathology, 2010
- Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AMLBlood, 2009
- Diagnostic ExerciseVeterinary Pathology, 2009
- Deletion ofIKZF1and Prognosis in Acute Lymphoblastic LeukemiaThe New England Journal of Medicine, 2009