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Molecular and Cellular Biology, December 2000, p. 8655-8666, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification and Characterization of an Activating TrkA Deletion Mutation in Acute Myeloid Leukemia

Gary W. Reuther,1,* Que T. Lambert,2 Michael A. Caligiuri,3 and Channing J. Der2,4

Lineberger Comprehensive Cancer Center,1 Department of Pharmacology,2 and Curriculum in Genetics,4 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, and The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 432103

Received 6 April 2000/Returned for modification 10 May 2000/Accepted 22 August 2000

In this study, we utilized retroviral transfer of cDNA libraries in order to identify oncogenes that are expressed in acute myeloid leukemia (AML). From screens using two different cell types as targets for cellular transformation, a single cDNA encoding a variant of the TrkA protooncogene was isolated. The protein product of this protooncogene, TrkA, is a receptor tyrosine kinase for nerve growth factor. The isolated transforming cDNA encoded a TrkA protein that contains a 75-amino-acid deletion in the extracellular domain of the receptor and was named Delta TrkA. Delta TrkA readily transformed fibroblast and epithelial cell lines. The deletion resulted in activation of the tyrosine kinase domain leading to constitutive tyrosine phosphorylation of the protein. Expression of Delta TrkA in cells led to the constitutive activation of intracellular signaling pathways that include Ras, extracellular signal-regulated kinase/mitogen-activated protein kinase, and Akt. Importantly, Delta TrkA altered the apoptotic and growth properties of 32D myeloid progenitor cells, suggesting Delta TrkA may have contributed to the development and/or maintenance of the myeloid leukemia from which it was isolated. Unlike Bcr-Abl, expression of Delta TrkA did not activate Stat5 in these cells. We have detected expression of Delta TrkA in the original AML sample by reverse transcriptase PCR and by Western blot analysis. While previous TrkA mutations identified from human tumors involved fusion to other proteins, this report is the initial demonstration that deletions within TrkA may play a role in human cancers. Finally, this report is the first to indicate mutations in TrkA may contribute to leukemogenesis.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Campus Box 7295, Chapel Hill, NC 27599-7295. Phone: (919) 962-1057. Fax: (919) 966-0162. E-mail: greuther{at}med.unc.edu.

Molecular and Cellular Biology, December 2000, p. 8655-8666, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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