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

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1246-1254
Number of pages9
JournalLeukemia Research
Volume39
Issue number11
DOIs
StatePublished - May 13 2015

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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