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

93 Citations (Scopus)

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

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Hematologic Neoplasms
Protein-Tyrosine Kinases
Animals
Fusion reactions
Leukemia, Myelomonocytic, Chronic
Animal Diseases
Genetically Modified Animals
Myeloid Leukemia
Protein Kinase Inhibitors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transgenic Mice
Immunoglobulins
Tumors
Neoplasms
Proteins
Cells
Phenotype
Mutation
Molecules
Survival

ASJC Scopus subject areas

  • Hematology

Cite this

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

TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. / Tomasson, Michael H.; Williams, Ifor R.; Hasserjian, Robert; Udomsakdi, Chirayu; McGrath, Shannon M.; Schwaller, Juerg; Druker, Brian; Gilliland, D. Gary.

In: Blood, Vol. 93, No. 5, 01.03.1999, p. 1707-1714.

Research output: Contribution to journalArticle

Tomasson, MH, Williams, IR, Hasserjian, R, Udomsakdi, C, McGrath, SM, Schwaller, J, Druker, B & Gilliland, DG 1999, 'TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor', Blood, vol. 93, no. 5, pp. 1707-1714.
Tomasson MH, Williams IR, Hasserjian R, Udomsakdi C, McGrath SM, Schwaller J et al. TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. Blood. 1999 Mar 1;93(5):1707-1714.
Tomasson, Michael H. ; Williams, Ifor R. ; Hasserjian, Robert ; Udomsakdi, Chirayu ; McGrath, Shannon M. ; Schwaller, Juerg ; Druker, Brian ; Gilliland, D. Gary. / TEL/PDGFβR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. In: Blood. 1999 ; Vol. 93, No. 5. pp. 1707-1714.
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