Hsp32: MASTer of KIT? Free

In this issue of Blood, Kondo and colleagues analyze the role of Hsp32 as a survival factor for mast cells (MCs), and demonstrate that Hsp32-targeting drugs might be used as therapy for mastocytosis.

Growth, differentiation, and survival of MCs are mainly under the control of stem-cell factor (SCF), the ligand of KIT. Ligation of KIT, a tyrosine kinase (TK) receptor, is associated with receptor dimerization and followed by a complex cascade of signaling pathways.

Mastocytoses are rare diseases characterized by an increased number of MCs in one or several organs. In systemic mastocytosis (SM), neoplastic MCs accumulate in various internal organs. In a majority of patients with SM, including those with the aggressive form (ASM), or with mast-cell leukemia (MCL), an acquired and activating KIT point mutation is detectable, mostly the mutation D816V. Patients with ASM or MCL have a bad prognosis because they respond poorly to conventional drugs. For this reason, drugs that inhibit specifically the TK activity of KIT D816V have been developed. Drugs such as PKC412 have been found effective in vitro and even in vivo. However, due to possible emergence of resistance, these inhibitors alone might not be sufficient to induce long-lasting responses in ASM/MCL. Therefore, efforts are currently being made to identify additional therapeutic targets in neoplastic MCs.

Kondo and colleagues show that heat shock protein 32 (Hsp32) is an important survival factor in neoplastic MCs. First, they provide evidence that neoplastic MCs (primary cells and HMC-1 cells) express Hsp32 mRNA and protein. Of note, using Ba/F3 cells with doxycycline-inducible expression of KIT D816V or wild-type (WT) or cultured human MCs, they demonstrate that not only KIT D816V but also KIT WT increase Hsp32 promoter activity. Interestingly, a similar phenomenon is not seen in other (leukemic) KIT⁺ cells. In further experiments, the authors have observed, using PKC412 or imatinib (a KIT WT inhibitor), that increase in the expression of Hsp32 in various cell types can be counteracted by the inhibitor of the type of KIT expressed by the cells. After that, the authors have addressed the question of the signaling pathways involved in KIT D816V–mediated promotion of the expression of Hsp32. They show that, if the main pathway involved is PI3-kinase, other pathways, such as MEK, are also involved. Furthermore, elegant experiments conducted here lead to the conclusion that, because overexpression of Hsp32 is associated with a decrease in PKC412-induced apoptosis, Hsp32 might be considered as a cytoprotector against KIT-targeting drugs. Finally, Kondo and colleagues show that pharmacologic inhibitors of Hsp32 have apoptotic effects on MCs (see figure) and a synergistic inhibitory effect with PKC412 on the growth of neoplastic MCs.

Targeted therapies such as PKC412 might provide an alternative and more efficient approach to treat those patients with ASM/MCL resistant to classic cytoreductive agents. However, long-term use of such compounds might lead to drug resistance, as observed with imatinib for chronic myeloid leukemia. The work presented by Kondo and colleagues has the merit to propose an elegant approach to overcome such resistance in ASM/MCL with specific and nontoxic Hsp32 inhibitors.