Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder - PubMed (original) (raw)

Review

Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder

Anindya Chatterjee et al. Oncotarget. 2015.

Abstract

Although more than 90% systemic mastocytosis (SM) patients express gain of function mutations in the KIT receptor, recent next generation sequencing has revealed the presence of several additional genetic and epigenetic mutations in a subset of these patients, which confer poor prognosis and inferior overall survival. A clear understanding of how genetic and epigenetic mutations cooperate in regulating the tremendous heterogeneity observed in these patients will be essential for designing effective treatment strategies for this complex disease. In this review, we describe the clinical heterogeneity observed in patients with mastocytosis, the nature of relatively novel mutations identified in these patients, therapeutic strategies to target molecules downstream from activating KIT receptor and finally we speculate on potential novel strategies to interfere with the function of not only the oncogenic KIT receptor but also epigenetic mutations seen in these patients.

Keywords: KIT mutations; alternative targets in mastocytosis; mastocytosis; myeloproliferative disorder; signaling pathways in mastocytosis.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. Targeting various downstream signaling pathways from mutated KIT D816V receptors are depicted

PI3K mediated activation of RAS-MAPK-JNK pathway, AKT-ERK and ATK-mTORC2 pathway leads to survival of neoplastic MCs. Recent studies highlight newer pathways mediated by SHP2, FAK, ROCK are described with corresponding inhibitors that hold promise. (1) SHP2 and P13K/GAB2 induced AKT/ERK activation can be inhibited using SHP2 specific inhibitor IIBO8, (2) FAK/TIAM1/RAC1/PAK1 mediated nuclear translocation of active STAT5 in SM patients can be inhibited by targeting FAK and PAK1 (4) with inhibitors, (3) PI3K mediated activation of RAC1 via VAV1 can be targeted using novel RAC1 inhibitor Ehop-016, (5) PI3K/RHOA mediated activation of ROCK1 can be targeted by inhibitor H-1152 against ROCK1, (6) targeting PI3K using inhibitors that have shown promise in other malignancies [69], (7) targeting AKT (GSK2141795), (8) inhibiting JAK with Roxolitinib, Lestaurtinib, Pacritinib, and (9) targeting epigenetic regulators ASXL1, DNMT3A and TET2 by 5-azacytidine (5′-AZA) and 5-aza-2′ deoxycytidine (Decitabine/DAC).

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