Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion

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Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. / Austen, Belinda; Skowronska, Anna; [No Value], [No Value]; Powell, Judith; Gardiner, A; Oscier, D; Majid, A; Dyer, M; Siebert, R; Taylor, Alexander; Moss, Paul; Stankovic, Tatjana.

In: Journal of Clinical Oncology, Vol. 25, No. 34, 01.12.2007, p. 5448-57.

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@article{1b5f03748b4341ef993c8e25d03844f4,
title = "Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion",
abstract = "PURPOSE: The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele. METHODS: The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome. RESULTS: We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P = .0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion. CONCLUSION: CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.",
author = "Belinda Austen and Anna Skowronska and {[No Value]}, {[No Value]} and Judith Powell and A Gardiner and D Oscier and A Majid and M Dyer and R Siebert and Alexander Taylor and Paul Moss and Tatjana Stankovic",
year = "2007",
month = dec,
day = "1",
doi = "10.1200/JCO.2007.11.2649",
language = "English",
volume = "25",
pages = "5448--57",
journal = "Journal of Clinical Oncology ",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "34",

}

RIS

TY - JOUR

T1 - Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion

AU - Austen, Belinda

AU - Skowronska, Anna

AU - [No Value], [No Value]

AU - Powell, Judith

AU - Gardiner, A

AU - Oscier, D

AU - Majid, A

AU - Dyer, M

AU - Siebert, R

AU - Taylor, Alexander

AU - Moss, Paul

AU - Stankovic, Tatjana

PY - 2007/12/1

Y1 - 2007/12/1

N2 - PURPOSE: The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele. METHODS: The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome. RESULTS: We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P = .0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion. CONCLUSION: CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.

AB - PURPOSE: The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele. METHODS: The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome. RESULTS: We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P = .0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion. CONCLUSION: CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.

U2 - 10.1200/JCO.2007.11.2649

DO - 10.1200/JCO.2007.11.2649

M3 - Article

C2 - 17968022

VL - 25

SP - 5448

EP - 5457

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 34

ER -