The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways

Martin Carroll; Michael H Tomasson; George F Barker; Todd R Golub; D. Gary Gilliland

doi:10.1073/pnas.93.25.14845

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The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways

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The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways

Martin Carroll, Michael H Tomasson, George F Barker, Todd R Golub and D. Gary Gilliland

Proceedings of the National Academy of Sciences - PNAS, Vol.93(25), pp.14845-14850

12/10/1996

DOI: 10.1073/pnas.93.25.14845

PMCID: PMC26224

PMID: 8962143

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Abstract

The TEL/PDGFβR fusion protein is the product of the t(5;12) translocation in patients with chronic myelomonocytic leukemia. The TEL/PDGFβR is an unusual fusion of a putative transcription factor, TEL, to a receptor tyrosine kinase. The translocation fuses the amino terminus of TEL, containing the helix-loop-helix (HLH) domain, to the transmembrane and cytoplasmic domain of the PDGFβR. We hypothesized that TEL/PDGFβR self-association, mediated by the HLH domain of TEL, would lead to constitutive activation of the PDGFβR tyrosine kinase domain and cellular transformation. Analysis of in vitro-translated TEL/PDGFβR confirmed that the protein self-associated and that self-association was abrogated by deletion of 51 aa within the TEL HLH domain. In vivo, TEL/PDGFβR was detected as a 100-kDa protein that was constitutively phosphorylated on tyrosine and transformed the murine hematopoietic cell line Ba/F3 to interleukin 3 growth factor independence. Transformation of Ba/F3 cells required the HLH domain of TEL and the kinase activity of the PDGFβR portion of the fusion protein. Immunoblotting demonstrated that TEL/PDGFβR associated with multiple signaling molecules known to associate with the activated PDGFβR, including phospholipase C γ1, SHP2, and phosphoinositol-3-kinase. TEL/PDGFβR is a novel transforming protein that self-associates and activates PDGFβR-dependent signaling pathways. Oligomerization of TEL/PDGFβR that is dependent on the TEL HLH domain provides further evidence that the HLH domain, highly conserved among ETS family members, is a self-association motif.

Biological Sciences

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Title: Subtitle: The TEL/platelet-derived growth factor β receptor (PDGFβR) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGFβR kinase-dependent signaling pathways
Creators: Martin Carroll - Division of Hematology and Oncology, Brigham and Women’s Hospital
Michael H Tomasson - Division of Hematology and Oncology, Brigham and Women’s Hospital
George F Barker - Division of Hematology and Oncology, Brigham and Women’s Hospital
Todd R Golub - Division of Hematology and Oncology, Brigham and Women’s Hospital
D. Gary Gilliland - Division of Hematology and Oncology, Brigham and Women’s Hospital
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.93(25), pp.14845-14850
DOI: 10.1073/pnas.93.25.14845
PMID: 8962143
PMCID: PMC26224
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 12/10/1996
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094514002771

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