Molecular Defects in Mastocytosis: KIT and Beyond KIT

Key points

Critical roles of SCF and KIT in the development and biology of MCs

Mice with loss-of-function mutations affecting either synthesis of SCF (Sl/Sld mice) or Kit (W/Wv mice) are virtually devoid of MCs, showing the importance of the SCF/Kit axis in MCs.¹¹ In contrast, gain-of-function mutations in the KIT proto-oncogene are associated with enhanced survival and autonomous growth of MCs and their progenitors.¹² In addition, the injection of SCF increases the number of MCs by more than 100 times near the site of injection.¹³ MCs are the only terminally

Classification of mastocytosis

Mastocytosis is schematically divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM).⁶ Localized MC tumors (ie, mastocytomas and MC sarcoma [MCS]) are rare.³² CM is usually diagnosed in childhood.³³ However, in most adult patients, the disease is systemic (SM), although the skin is often also affected.³⁴

In patients with SM, the diagnosis is usually established by BM investigation using classic staining and specific tryptase stains.³⁵ Besides, apart from the BM, other organs,

Involvement of KIT defects in mastocytosis

Since SCF was identified as the major cytokine responsible for MC proliferation, various teams have investigated whether increased secretion of SCF could be involved in the pathophysiology of mastocytosis. No convincing data appeared, and investigations were thereafter conducted on its receptor KIT, which was reported to be responsible for autonomous growth of cell lines harboring KIT mutations, by constitutively activating downstream pathways in the absence of SCF.46, 47 Neoplastic MCs of

Abnormal signaling evoked by the KIT D816V oncogenic mutant

This section focuses on the signaling pathways evoked by the KIT D816V mutant receptor (Fig. 3), which is the most prominently KIT mutant found in all the variants of SM.

Although the mechanism behind the constitutive activation of the KIT D816V mutant receptor is still not fully understood, 1 possibility is that mutation within the phosphotransferase domain (PTD) results in a structural change that relieves autoinhibitory mechanisms. This hypothesis remains speculative, because no crystal

Consequences of the various defects in KIT for targeted therapy

There are strong changes in the sensitivity of KIT mutants to TK inhibitors (TKIs) type II (eg, imatinib or masitinib) compared with KIT WT.⁸⁷ Thus, before using targeted therapies aiming to inhibit KIT TK activity for the treatment of patients with SM, it is mandatory to know exactly the KIT mutational status of each patient. However, even with adequate targeting of the KIT mutant, the results could be deceiving, and no complete remission should be obtained with SM, particularly in advSM. For

Summary and future considerations

In SM, the KIT D816V mutant is detected in most (>90%) patients.⁴⁵ Although TKIs specific for KIT D816V have shown excellent activity toward KIT D816V in vitro,91, 118 these compounds have only modest activity in vivo. One possible explanation could be that the molecular pathogenesis of SM, particularly in advSM is more complex than the presence of a single gene defect in KIT and that additional genetic defects could also influence the severity and progression of SM. This theory might explain