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 Lampidis, Julio Barredo

Research output: Contribution to journalArticle

4 Citations (Scopus)

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)
JournalLeukemia Research
DOIs
StateAccepted/In press - May 13 2015

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Down-Regulation
AMP-Activated Protein Kinases
MAP Kinase Signaling System
Glucose
Apoptosis
Glycolysis
Glycosylation
Cell Death
Cell Line

Keywords

  • 2-deoxy-d-glucose
  • Acute lymphoblastic leukemia
  • AMPK
  • Apoptosis
  • BCR-ABL+
  • Combination targeted therapy
  • Dasatinib
  • EIF2α
  • Energy stress
  • ER stress
  • ERK
  • Imatinib
  • Leukemia
  • Mcl-1
  • ShRNA
  • Tyrosine kinase inhibitors
  • UPR

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress. / Leclerc, Guy J.; DeSalvo, Joanna; Du, Jianfeng; Gao, Ningguo; Leclerc, Gilles M.; Lehrman, Mark A.; Lampidis, Theodore; Barredo, Julio.

In: Leukemia Research, 13.05.2015.

Research output: Contribution to journalArticle

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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.",
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author = "Leclerc, {Guy J.} and Joanna DeSalvo and Jianfeng Du and Ningguo Gao and Leclerc, {Gilles M.} and Lehrman, {Mark A.} and Theodore Lampidis and Julio Barredo",
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T1 - Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress

AU - Leclerc, Guy J.

AU - DeSalvo, Joanna

AU - Du, Jianfeng

AU - Gao, Ningguo

AU - Leclerc, Gilles M.

AU - Lehrman, Mark A.

AU - Lampidis, Theodore

AU - Barredo, Julio

PY - 2015/5/13

Y1 - 2015/5/13

N2 - 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.

AB - 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.

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KW - Apoptosis

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KW - Energy stress

KW - ER stress

KW - ERK

KW - Imatinib

KW - Leukemia

KW - Mcl-1

KW - ShRNA

KW - Tyrosine kinase inhibitors

KW - UPR

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