Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress.
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.
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.
Guy J
GJ
Leclerc
Department of Pediatrics, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Joanna
J
DeSalvo
Department of Pediatrics, Division of Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Jianfeng
J
Du
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Ningguo
N
Gao
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.
Gilles M
GM
Leclerc
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Mark A
MA
Lehrman
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.
Theodore J
TJ
Lampidis
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.
Julio C
JC
Barredo
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