Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib

Anna Guarini; Nadia Peragine; Monica Messina; Marilisa Marinelli; Caterina Ilari; Luciana Cafforio; Sara Raponi; Silvia Bonina; Paola Mariglia; Francesca R. Mauro; Gianluca Gaidano; Ilaria Del Giudice; Robin Foà

doi:10.1111/bjh.15613

Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib

Anna Guarini, Nadia Peragine, Monica Messina, Marilisa Marinelli, Caterina Ilari, Luciana Cafforio, Sara Raponi, Silvia Bonina, Paola Mariglia, Francesca R. Mauro, Gianluca Gaidano, Ilaria Del Giudice, Robin Foà

Dipartimento di Medicina Traslazionale

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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.

Lingua originale	Inglese
pagine (da-a)	392-396
Numero di pagine	5
Rivista	British Journal of Haematology
Volume	184
Numero di pubblicazione	3
DOI	https://doi.org/10.1111/bjh.15613
Stato di pubblicazione	Pubblicato - feb 2019

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10.1111/bjh.15613

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title = "Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib",

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 = "BCL2 inhibitor, BCR activity, BTK inhibitor, CLL, TP53 mutation",

author = "Anna Guarini and Nadia Peragine and Monica Messina and Marilisa Marinelli and Caterina Ilari and Luciana Cafforio and Sara Raponi and Silvia Bonina and Paola Mariglia and Mauro, {Francesca R.} and Gianluca Gaidano and {Del Giudice}, Ilaria and Robin Fo{\`a}",

note = "Publisher Copyright: {\textcopyright} 2018 British Society for Haematology and John Wiley & Sons Ltd",

year = "2019",

month = feb,

doi = "10.1111/bjh.15613",

language = "English",

volume = "184",

pages = "392--396",

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TY - JOUR

T1 - Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib

AU - Guarini, Anna

AU - Peragine, Nadia

AU - Messina, Monica

AU - Marinelli, Marilisa

AU - Ilari, Caterina

AU - Cafforio, Luciana

AU - Raponi, Sara

AU - Bonina, Silvia

AU - Mariglia, Paola

AU - Mauro, Francesca R.

AU - Gaidano, Gianluca

AU - Del Giudice, Ilaria

AU - Foà, Robin

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - BCL2 inhibitor

KW - BCR activity

KW - BTK inhibitor

KW - CLL

KW - TP53 mutation

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U2 - 10.1111/bjh.15613

DO - 10.1111/bjh.15613

M3 - Article

SN - 0007-1048

VL - 184

SP - 392

EP - 396

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 3

ER -

Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib

Abstract

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