Abstract
T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.
Keywords:
MCL1; MCL1 inhibitors; Ponatinib; Protein degradation; T315I-positive Ph+ leukemia cell; c-myc.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Cell Death / drug effects
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Cell Death / genetics
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Cell Line, Tumor
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Cyclin D2 / genetics
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Cyclin D2 / metabolism*
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Drug Resistance, Neoplasm / genetics
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Drug Synergism
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Imatinib Mesylate / pharmacology*
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Imidazoles / pharmacology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leupeptins / pharmacology
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Macrocyclic Compounds / pharmacology
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol 3-Kinases / pharmacology
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Phosphoinositide-3 Kinase Inhibitors / pharmacology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Protein Phosphatase 2 / metabolism
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Pyridazines / pharmacology*
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Pyrroles / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Wortmannin / pharmacology
Substances
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AZD5991
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Antineoplastic Agents
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CCND2 protein, human
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Cyclin D2
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Imidazoles
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Leupeptins
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MCL1 protein, human
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MYC protein, human
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Macrocyclic Compounds
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Pyridazines
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Pyrroles
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marinopyrrole A
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ponatinib
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Imatinib Mesylate
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Glycogen Synthase Kinase 3
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Protein Phosphatase 2
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Wortmannin