High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib

Haifa Kathrin Al-Ali, Michael Heinrich, Thoralf Lange, Rainer Krahl, Matthias Mueller, Christel Müller, Dietger Niederwieser, Brian Druker, Michael Werner Nikolaus Deininger

Research output: Contribution to journalArticle

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Abstract

Imatinib, a specific inhibitor of the Abl, Kit and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is effective in all phases of chronic myelogenous leukemia. While responses in chronic phase are usually durable, resistance frequently develops in patients with advanced disease after an initial response. Several mechanisms of resistance have been demonstrated in vivo, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene. We analyzed cytogenetics and screened for mutations of the BCR-ABL kinase domain as well as the activation loops of KIT and PDGFRA and B in 49 patients with CML or Ph-positive acute lymphoblastic leukemia with resistance to imatinib. Mutations in the kinase domain of BCR-ABL were detected in 51.6% of patients with secondary resistance but not in patients with primary resistance. Three of these mutations have not been described before (T315D, F359D and D276G). By contrast, KIT and PDGFRA and B were consistently wildtype. Clonal evolution prior to imatinib was present in 68.8% of patients with primary resistance and in 45.5% with secondary resistance. Additional cytogenetic aberrations developed in 18.2% of patients at the time of relapse. Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of KIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.

Original languageEnglish (US)
Pages (from-to)55-60
Number of pages6
JournalHematology Journal
Volume5
Issue number1
DOIs
StatePublished - 2004

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Platelet-Derived Growth Factor Receptors
Phosphotransferases
Mutation
Incidence
Clonal Evolution
Leukemia, Myeloid, Chronic Phase
Platelet-Derived Growth Factor beta Receptor
Imatinib Mesylate
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cytogenetics
Chromosome Aberrations
Recurrence

Keywords

  • Chronic myeloid leukemia
  • Drug resistance
  • Imatinib
  • Kinase domain mutations

ASJC Scopus subject areas

  • Hematology

Cite this

High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. / Al-Ali, Haifa Kathrin; Heinrich, Michael; Lange, Thoralf; Krahl, Rainer; Mueller, Matthias; Müller, Christel; Niederwieser, Dietger; Druker, Brian; Deininger, Michael Werner Nikolaus.

In: Hematology Journal, Vol. 5, No. 1, 2004, p. 55-60.

Research output: Contribution to journalArticle

Al-Ali, Haifa Kathrin ; Heinrich, Michael ; Lange, Thoralf ; Krahl, Rainer ; Mueller, Matthias ; Müller, Christel ; Niederwieser, Dietger ; Druker, Brian ; Deininger, Michael Werner Nikolaus. / High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. In: Hematology Journal. 2004 ; Vol. 5, No. 1. pp. 55-60.
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AU - Lange, Thoralf

AU - Krahl, Rainer

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AU - Müller, Christel

AU - Niederwieser, Dietger

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AU - Deininger, Michael Werner Nikolaus

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