Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia.
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.
Gunby
Rosalind Helen
RH
Oncogenic Fusion Protein Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy. rosalind.gunby@istitutotumori.mi.it
Cazzaniga
Giovanni
G
Tassi
Elena
E
Le Coutre
Philipp
P
Pogliani
Enrico
E
Specchia
Giorgina
G
Biondi
Andrea
A
Gambacorti-Passerini
Carlo
C
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
D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; C120888:TEL-PDGFRbeta fusion protein, human; D000068877:Imatinib Mesylate