TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor

Michael H. Tomasson, Ifor R. Williams, Robert Hasserjian, Chirayu Udomsakdi, Shannon M. McGrath, Juerg Schwaller, Brian Druker, D. Gary Gilliland

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

The TEL/PDGFβR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFβR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFβR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFβR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFβR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFβR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFβR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase-mediated malignancies both early in the course of disease and after the development of additional transforming mutations.

Original languageEnglish (US)
Pages (from-to)1707-1714
Number of pages8
JournalBlood
Volume93
Issue number5
StatePublished - Mar 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Tomasson, M. H., Williams, I. R., Hasserjian, R., Udomsakdi, C., McGrath, S. M., Schwaller, J., Druker, B., & Gilliland, D. G. (1999). TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. Blood, 93(5), 1707-1714.