Neoplasia driven by mutant c-KIT is mediated by intracellular, not plasma membrane, receptor signaling.
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 KIT(D816V) (hKIT(D816V))-mediated leukemia, we uncovered an unexpected relationship between cellular transformation and intracellular trafficking. We found that transport of hKIT(D816V) 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 KIT(D816V) 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 hKIT(D816V) failed to induce disease in mice, while expression of either Golgi-localized HyKIT(D816V) or cytosol-localized, ectodomain-deleted KIT(D816V) 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 KIT(D816V).
Xiang
Zhifu
Z
Washington University School of Medicine, Campus Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Kreisel
Frederike
F
Cain
Jennifer
J
Colson
AnnaLynn
A
Tomasson
Michael H
MH
D000818:Animals; D016026:Bone Marrow Transplantation; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction
D019009:Proto-Oncogene Proteins c-kit