c-KIT and Gastrointestinal Stromal Tumors (GISTs)

Stefanie Chua

30 March 2004

What is KIT?

• Transmembrane type III tyrosine kinase receptor

• c-KIT is the cellular homologue of v-KIT

• Maps to chromosome 4 (4q11-12)

Where is KIT found?

• Hematopoietic stem cells

• Mast cells

• Melanocytic cells

• Germ cells

• Gametophytes

• **Interstitial cells of Cajal (ICC)

Structure of KIT

• Extracellular domain• Transmembrane

domain• Intracellular domain

• Mutations are typically found in the kinase domain

Ligand: SCF

• Ligand for KIT: stem cell factor (SCF) or Steel• It is found on…

• bone marrow stroma cells

• Fibroblasts

• Keratinocytes

• intestinal epithelial cells

• Sertoli’s cells

• granulosa cells

KIT Activation

Knockout Mice• Homozygous recessive mouse: dies within days

because of macrocytic anemia• Heterozygous mouse: defect in pigmentation

with white spotting phenotype, piebaldism.

KIT mutation

• Like most RTKs, KIT kinase has multiple levels of control, therefore, a number of phenotypic changes are observed because KIT is found in a number of different cells including stem and germ cells.

• These types of mutations result in a loss of kinase function.

• BUT… gain of function mutations are involved in the induction of tumors of ICCs to form GISTs

KIT and SCF

• Heterozygous for a loss of function mutation

• Only have half of the normal amount of KIT gene product• Shortage of red blood

cells

• Shortage of pigment cells

• Shortage of germ cells

Gastrointestinal Stromal Tumors (GISTs)

• GISTs develop from ICCs

• GISTs and ICCs are double positive for KIT and CD34.

GISTs in relation to KIT

• 84 – 100% of GISTs express constitutively active KIT

• KIT oncogenic activation occurs in the early stages of benign GIST formation• Not dependent on binding of KIT ligand• Have structural changes that favor receptor

oligomerization and cross phosphorylation even in the absence of ligand

• When mutation occurs in KIT, the tyrosine kinase activity of KIT is constitutively gained without the binding of SCF.

Treatment: Gleevac

• Chemotherapy and radiation are not conducive to the treatment GISTs

• It was found that KIT oncoproteins have the same active enzymatic site as native KIT. Therefore, kinase inhibitors like STI-571 (Gleevac)bind well and are effective inhibitors of constitutively activated molecules.

Works CitedHirota S. Gastrointestinal stromal tumors: their origin and cause. [Review]

International Journal of Clincal Oncology. 6(1): 1-5, 2001 Feb. Taylor ML. Metcalfe DD. Kit signal transduction [Review] Hematology –

Oncology Clinics of North America. 14(3): 517-25, 2000 Jun.Heinrich MC. Rubin BP. Longle BJ. Fletcher JA. Biology and genetic aspects

of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. [Review] Human Pathology. 33(5): 484 –95, 2002 May.

Ashman LK. The biology of stem cell factor and its receptor C-kit. [Review] International Journal of Biochemistry and Cell Biology. 31(1999): 1037-1051, 1999 Feb.

Longley BJ. Reguera MJ. Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. [Review] Leukemia Research. 25(2001): 571-576, 2001 Jan.

Waskow C. Rodewald HR. Lymphocyte development in neonatal and adult c-Kit-deficient mice. [Review] Advances in Experimental Medicine and Biology. 512:1-10, 2002.

Gilbert, Scott F. Developmental Biology, 7th ed. 2003: USA. Sinauer Associates, Inc.