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Molecular and Cellular Biology, January 2007, p. 267-282, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01153-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Neoplasia Driven by Mutant c-KIT Is Mediated by Intracellular, Not Plasma Membrane, Receptor Signaling{triangledown}

Zhifu Xiang,1 Frederike Kreisel,2 Jennifer Cain,1 AnnaLynn Colson,1 and Michael H. Tomasson1*

Department of Internal Medicine, Division of Oncology,1 Department of Pathology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, Missouri 631102

Received 27 June 2006/ Returned for modification 26 July 2006/ Accepted 9 October 2006

Activating mutations in c-KIT are associated with gastrointestinal stromal tumors, mastocytosis, and acute myeloid leukemia. In attempting to establish a murine model of human KITD816V (hKITD816V)-mediated leukemia, we uncovered an unexpected relationship between cellular transformation and intracellular trafficking. We found that transport of hKITD816V protein was blocked at the endoplasmic reticulum in a species-specific fashion. We exploited these species-specific trafficking differences and a set of localization domain-tagged KIT mutants to explore the relationship between subcellular localization of mutant KIT and cellular transformation. The protein products of fully transforming KIT mutants localized to the Golgi apparatus and to a lesser extent the plasma membrane. Domain-tagged KITD816V targeted to the Golgi apparatus remained constitutively active and transforming. Chemical inhibition of intracellular transport demonstrated that Golgi localization is sufficient, but plasma membrane localization is dispensable, for downstream signaling mediated by KIT mutation. When expressed in murine bone marrow, endoplasmic reticulum-localized hKITD816V failed to induce disease in mice, while expression of either Golgi-localized HyKITD816V or cytosol-localized, ectodomain-deleted KITD816V uniformly caused fatal myeloproliferative diseases. Taken together, these data demonstrate that intracellular, non-plasma membrane receptor signaling is sufficient to drive neoplasia caused by mutant c-KIT and provide the first animal model of myelomonocytic neoplasia initiated by human KITD816V.

* Corresponding author. Mailing address: Washington University School of Medicine, Campus Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 362-9350. Fax: (314) 362-9333. E-mail: tomasson{at}wustl.edu.

{triangledown} Published ahead of print on 23 October 2006.

Molecular and Cellular Biology, January 2007, p. 267-282, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01153-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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