Abstract
TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53-M CLL patients.
Keywords:
CLL; BCL2 inhibitor; BCR activity; BTK inhibitor; TP53 mutation.
© 2018 British Society for Haematology and John Wiley & Sons Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adult
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Aged
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Aged, 80 and over
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Apoptosis / drug effects
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Down-Regulation / drug effects*
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Male
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Middle Aged
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Mutation*
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Piperidines
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology*
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Receptors, Antigen, B-Cell / biosynthesis*
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Sulfonamides / pharmacology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Piperidines
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Pyrazoles
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Pyrimidines
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Receptors, Antigen, B-Cell
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Sulfonamides
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TP53 protein, human
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Tumor Suppressor Protein p53
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ibrutinib
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Adenine
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venetoclax