Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

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Abstract

Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

Original languageEnglish (US)
Pages (from-to)1931-1939
Number of pages9
JournalBlood
Volume104
Issue number7
DOIs
StatePublished - Oct 1 2004

Fingerprint

abl Genes
Platelet-Derived Growth Factor beta Receptor
Mutation
Pharmaceutical Preparations
Genes
Chromosomes
Proto-Oncogene Proteins c-kit
Proto-Oncogene Proteins c-sis
Mastocytosis
Platelet-Derived Growth Factor Receptors
Myeloproliferative Disorders
Chromosome Deletion
Polycythemia Vera
Primary Myelofibrosis
Investigational Therapies
Eosinophilia
Hematologic Neoplasms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Acute Myeloid Leukemia
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Hematology

Cite this

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. / Pardanani, Animesh D; Tefferi, Ayalew.

In: Blood, Vol. 104, No. 7, 01.10.2004, p. 1931-1939.

Research output: Contribution to journalArticle

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