Table 1.

Data supporting the important roles of events other than KIT mutations in mastocytosis pathogenesis.

	Data and References
1	Although both childhood- and adult-onset mastocytosis are associated with activating KIT mutations, the clinical presentation and outcomes of these two conditions differ (a skin-limited disease that spontaneously regresses with age vs. persistent, multi-organ involvement, often with a concurrent non-MC hematologic neoplasm) [3,23]. KIT mutations alone cannot explain the full clinical spectrum of SM.
2	KIT D816V does not activate mast cells to release proinflammatory mediators [24].
3	KIT D816V mutation appears to be a late event in the pathogenesis of mastocytosis [8].
4	KIT D816V is a weak oncogene. For example, BaF3 cells with conditional expression of KIT D816V did not form tumors in nude mice [25].
5	KIT D816V is thought to promote MC differentiation and maturation rather than MC proliferation [5].
6	The retroviral-mediated expression of KIT D816V failed to induce SM in transplanted animals [21]. Only 29% of transgenic mice expressing human KIT D816V developed mastocytosis at an old age (>12 months) [22]. In addition, 50% of transgenic zebrafish expressing KIT D616V demonstrated a myeloproliferative disease phenotype, including features of ASM [26]. Although mastocytosis was observed in all transgenic mice expressing murine KitD814V (homolog of the human D816V mutant) in another model, the disease occurred significantly later and progressed slower when KitD814V was expressed in mature MCs [27]. Mastocytosis was not observed at all in transgenic mice expressing KitD814V in an earlier study [28].
7	Targeting KIT in SM may produce a substantial reduction in MC burden in some patients, however, treatment with KIT inhibitors alone, thus far, has been disappointing in most patients with mastocytosis [1], likely due to the development of resistance to kinase inhibitors [4,29]. A recently published study demonstrated a therapeutic benefit in patients with advanced SM associated with the use of midostaurin (PKC412), a multiple kinase inhibitor that inhibits KIT [11]; however, overall survival at 3 years was only 46%. Few, if any, patients achieved complete remission.