title: Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia.
abstract: OBJECTIVE
  Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome that has been associated with the expression of platelet-derived growth factor b receptor (PDGFRbeta) fusion proteins, namely TEL/PDGFRbeta. These fusion proteins possess a constitutive PDGFRbeta tyrosine kinase activity, leading to aberrant PDGFRbeta signaling and cellular transformation. The expression of PDGFRbeta fusions in CMML could have therapeutic relevance, as PDGFRb is inhibited by the selective tyrosine kinase inhibitor, imatinib. Here, we investigated the possibility of employing imatinib to treat CMML.
  
  
  METHODS
  We assessed the effect of imatinib on TEL/PDGFRbeta transformed cells in terms of proliferation, by trypan blue exclusion and 3H-thymidine uptake, and TEL/PDGFRbeta autophosphorylation by anti-phosphotyrosine immunoblotting. TEL/PDGFRbeta expression in mononuclear cells from the peripheral blood of 27 clinically diagnosed CMML patients was determined by reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  Imatinib potently inhibited the proliferation of TEL/PDGFRbeta transformed cells (IC50=7.5 nM), and TEL/PDGFRbeta kinase activity. However, TEL/PDGFRbeta expression was detected in only 1 of 27 CMML patients (4%, confidence intervals: 0-13%). Additionally, another PDGFRbeta fusion protein, Hip1/PDGFRbeta, had a similarly low incidence in the same samples: 1 of 25 (4%, confidence intervals: 0-14%).
  
  
  CONCLUSIONS
  Although imatinib represents an attractive therapeutic agent for neoplasias associated with abnormal PDGFRbeta signaling, the low frequency of the TEL/PDGFRbeta and Hip1/PDGFRbeta fusion proteins in CMML suggests that its application to this disease maybe limited. Detection of PDGFRbeta fusion genes in individual patients is necessary in order to employ this drug rationally in CMML.
authors.affiliation: Oncogenic Fusion Protein Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy. rosalind.gunby@istitutotumori.mi.it
authors.forename: Rosalind Helen
authors.initials: RH
authors.lastname: Gunby
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
authors.forename: Elena
authors.initials: E
authors.lastname: Tassi
authors.forename: Philipp
authors.initials: P
authors.lastname: Le Coutre
authors.forename: Enrico
authors.initials: E
authors.lastname: Pogliani
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D000818:Animals; D001549:Benzamides; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; C120888:TEL-PDGFRbeta fusion protein, human; D000068877:Imatinib Mesylate