Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

Juhura G. Almazi; Munther Alomari; Larissa Belov; O. Giles Best; Yandong Shen; Mark E. Graham; Stephen P. Mulligan; Richard I. Christopherson

doi:10.1080/15257770.2021.2013500

Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

Juhura G. Almazi, Munther Alomari, Larissa Belov, O. Giles Best, Yandong Shen, Mark E. Graham, Stephen P. Mulligan, Richard I. Christopherson

Research output: Contribution to journal › Article › peer-review

Abstract

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.

Original language	English
Pages (from-to)	314-320
Number of pages	7
Journal	Nucleosides, Nucleotides and Nucleic Acids
Volume	41
Issue number	3
Early online date	10 Dec 2021
DOIs	https://doi.org/10.1080/15257770.2021.2013500
Publication status	Published - 2022
Externally published	Yes

Keywords

Drug mechanism
Fludarabine
interactome
leukemia
p53

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines",

abstract = "Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin{\textquoteright}s lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.",

keywords = "Drug mechanism, Fludarabine, interactome, leukemia, p53",

author = "Almazi, {Juhura G.} and Munther Alomari and Larissa Belov and Best, {O. Giles} and Yandong Shen and Graham, {Mark E.} and Mulligan, {Stephen P.} and Christopherson, {Richard I.}",

year = "2022",

doi = "10.1080/15257770.2021.2013500",

language = "English",

volume = "41",

pages = "314--320",

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T1 - Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

AU - Almazi, Juhura G.

AU - Alomari, Munther

AU - Belov, Larissa

AU - Best, O. Giles

AU - Shen, Yandong

AU - Graham, Mark E.

AU - Mulligan, Stephen P.

AU - Christopherson, Richard I.

PY - 2022

Y1 - 2022

N2 - Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.

AB - Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.

KW - Drug mechanism

KW - Fludarabine

KW - interactome

KW - leukemia

KW - p53

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U2 - 10.1080/15257770.2021.2013500

DO - 10.1080/15257770.2021.2013500

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SN - 1525-7770

VL - 41

SP - 314

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JO - Nucleosides, Nucleotides and Nucleic Acids

JF - Nucleosides, Nucleotides and Nucleic Acids

IS - 3

ER -

Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

Abstract

Keywords

UN SDGs

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