Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress

Guy J Leclerc; Joanna DeSalvo; Jianfeng Du; Ningguo Gao; Gilles M Leclerc; Mark A Lehrman; Theodore J Lampidis; Julio C Barredo

doi:10.1016/j.leukres.2015.08.007

Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress

Leuk Res. 2015 Aug 20:S0145-2126(15)30360-X 10.1016/j.leukres.2015.08.007. doi: 10.1016/j.leukres.2015.08.007. Online ahead of print.

Authors

Guy J Leclerc¹, Joanna DeSalvo², Jianfeng Du², Ningguo Gao³, Gilles M Leclerc¹, Mark A Lehrman³, Theodore J Lampidis⁴, Julio C Barredo⁵

Affiliations

¹ Department of Pediatrics, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
² Department of Pediatrics, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
³ Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
⁴ Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
⁵ Department of Pediatrics, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33101, USA. Electronic address: jbarredo@miami.edu.

Abstract

BCR-ABL positive (+) acute lymphoblastic leukemia (ALL) accounts for ∼30% of cases of ALL. We recently demonstrated that 2-deoxy-d-glucose (2-DG), a dual energy (glycolysis inhibition) and ER-stress (N-linked-glycosylation inhibition) inducer, leads to cell death in ALL via ER-stress/UPR-mediated apoptosis. Among ALL subtypes, BCR-ABL+ ALL cells exhibited the highest sensitivity to 2-DG suggesting BCR-ABL expression may be linked to this increased vulnerability. To confirm the role of BCR-ABL, we constructed a NALM6/BCR-ABL stable cell line and found significant increase in 2-DG-induced apoptosis compared to control. We found that Mcl-1 was downregulated by agents inducing ER-stress and Mcl-1 levels correlated with ALL sensitivity. In addition, we showed that Mcl-1 expression is positively regulated by the MEK/ERK pathway, dependent on BCR-ABL, and further downregulated by combining ER-stressors with TKIs. We determined that energy/ER stressors led to translational repression of Mcl-1 via the AMPK/mTOR and UPR/PERK/eIF2α pathways. Taken together, our data indicate that BCR-ABL+ ALL exhibits heightened sensitivity to induction of energy and ER-stress through inhibition of the MEK/ERK pathway, and translational repression of Mcl-1 expression via AMPK/mTOR and UPR/PERK/eIF2α pathways. This study supports further consideration of strategies combining energy/ER-stress inducers with BCR-ABL TKIs for future clinical translation in BCR-ABL+ ALL patients.

Keywords: 2-deoxy-d-glucose; AMPK; Acute lymphoblastic leukemia; Apoptosis; BCR-ABL+; Combination targeted therapy; Dasatinib; ER stress; ERK; Energy stress; Imatinib; Leukemia; Mcl-1; Tyrosine kinase inhibitors; UPR; eIF2α; shRNA.

Abstract

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