BCR-ABL kinase domain mutations in chronic myeloid leukemia: Not quite enough to cause resistance to imatinib therapy?

Thoralf Lange, Byung Park, Stephanie G. Willis, Michael W N Deininger

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Patients with chronic myeloid leukemia (CML) treated with imatinib in early chronic phase tend to have durable remissions, but there is a high rate of relapse in patients with advanced disease. Mutations in the kinase domain of BCR-ABL that impair drug binding have been identified as the major mechanism of resistance. It is not known when exactly these mutations arise, but in some patients retrospective analysis of pretherapeutic samples demonstrated identical mutations, suggesting selection in the presence of drug. In the present study we have used a highly sensitive PCR assay to screen for kinase domain mutations in pretherapeutic samples from CML patients, irrespective of their subsequent response to imatinib. We find that kinase domain mutations are demonstrable in approximately 1/3 of patients with accelerated phase or blast crisis and that the presence of two copies of the Philadelphia chromosome is strongly correlated with mutation detection. Unexpectedly, kinase domain mutant clones were not invariably selected in the presence of drug, suggesting that additional mechanisms must contribute to a fully drug resistant leukemia.

Original languageEnglish (US)
Pages (from-to)1761-1766
Number of pages6
JournalCell Cycle
Volume4
Issue number12
StatePublished - Dec 2005

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutation
Pharmaceutical Preparations
Therapeutics
Chromosomes
Blast Crisis
Philadelphia Chromosome
Assays
Imatinib Mesylate
Leukemia
Clone Cells
Recurrence
Polymerase Chain Reaction

Keywords

  • Bcr-Abl
  • Chronic myeloid leukemia
  • Imatinib
  • Kinase domain mutations

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

BCR-ABL kinase domain mutations in chronic myeloid leukemia : Not quite enough to cause resistance to imatinib therapy? / Lange, Thoralf; Park, Byung; Willis, Stephanie G.; Deininger, Michael W N.

In: Cell Cycle, Vol. 4, No. 12, 12.2005, p. 1761-1766.

Research output: Contribution to journalArticle

Lange, Thoralf ; Park, Byung ; Willis, Stephanie G. ; Deininger, Michael W N. / BCR-ABL kinase domain mutations in chronic myeloid leukemia : Not quite enough to cause resistance to imatinib therapy?. In: Cell Cycle. 2005 ; Vol. 4, No. 12. pp. 1761-1766.
@article{bbd9de04a1b1483d97e006b731670519,
title = "BCR-ABL kinase domain mutations in chronic myeloid leukemia: Not quite enough to cause resistance to imatinib therapy?",
abstract = "Patients with chronic myeloid leukemia (CML) treated with imatinib in early chronic phase tend to have durable remissions, but there is a high rate of relapse in patients with advanced disease. Mutations in the kinase domain of BCR-ABL that impair drug binding have been identified as the major mechanism of resistance. It is not known when exactly these mutations arise, but in some patients retrospective analysis of pretherapeutic samples demonstrated identical mutations, suggesting selection in the presence of drug. In the present study we have used a highly sensitive PCR assay to screen for kinase domain mutations in pretherapeutic samples from CML patients, irrespective of their subsequent response to imatinib. We find that kinase domain mutations are demonstrable in approximately 1/3 of patients with accelerated phase or blast crisis and that the presence of two copies of the Philadelphia chromosome is strongly correlated with mutation detection. Unexpectedly, kinase domain mutant clones were not invariably selected in the presence of drug, suggesting that additional mechanisms must contribute to a fully drug resistant leukemia.",
keywords = "Bcr-Abl, Chronic myeloid leukemia, Imatinib, Kinase domain mutations",
author = "Thoralf Lange and Byung Park and Willis, {Stephanie G.} and Deininger, {Michael W N}",
year = "2005",
month = "12",
language = "English (US)",
volume = "4",
pages = "1761--1766",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "12",

}

TY - JOUR

T1 - BCR-ABL kinase domain mutations in chronic myeloid leukemia

T2 - Not quite enough to cause resistance to imatinib therapy?

AU - Lange, Thoralf

AU - Park, Byung

AU - Willis, Stephanie G.

AU - Deininger, Michael W N

PY - 2005/12

Y1 - 2005/12

N2 - Patients with chronic myeloid leukemia (CML) treated with imatinib in early chronic phase tend to have durable remissions, but there is a high rate of relapse in patients with advanced disease. Mutations in the kinase domain of BCR-ABL that impair drug binding have been identified as the major mechanism of resistance. It is not known when exactly these mutations arise, but in some patients retrospective analysis of pretherapeutic samples demonstrated identical mutations, suggesting selection in the presence of drug. In the present study we have used a highly sensitive PCR assay to screen for kinase domain mutations in pretherapeutic samples from CML patients, irrespective of their subsequent response to imatinib. We find that kinase domain mutations are demonstrable in approximately 1/3 of patients with accelerated phase or blast crisis and that the presence of two copies of the Philadelphia chromosome is strongly correlated with mutation detection. Unexpectedly, kinase domain mutant clones were not invariably selected in the presence of drug, suggesting that additional mechanisms must contribute to a fully drug resistant leukemia.

AB - Patients with chronic myeloid leukemia (CML) treated with imatinib in early chronic phase tend to have durable remissions, but there is a high rate of relapse in patients with advanced disease. Mutations in the kinase domain of BCR-ABL that impair drug binding have been identified as the major mechanism of resistance. It is not known when exactly these mutations arise, but in some patients retrospective analysis of pretherapeutic samples demonstrated identical mutations, suggesting selection in the presence of drug. In the present study we have used a highly sensitive PCR assay to screen for kinase domain mutations in pretherapeutic samples from CML patients, irrespective of their subsequent response to imatinib. We find that kinase domain mutations are demonstrable in approximately 1/3 of patients with accelerated phase or blast crisis and that the presence of two copies of the Philadelphia chromosome is strongly correlated with mutation detection. Unexpectedly, kinase domain mutant clones were not invariably selected in the presence of drug, suggesting that additional mechanisms must contribute to a fully drug resistant leukemia.

KW - Bcr-Abl

KW - Chronic myeloid leukemia

KW - Imatinib

KW - Kinase domain mutations

UR - http://www.scopus.com/inward/record.url?scp=29244436704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29244436704&partnerID=8YFLogxK

M3 - Article

C2 - 16319529

AN - SCOPUS:29244436704

VL - 4

SP - 1761

EP - 1766

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 12

ER -