SCF and IL-5 Synergize with FIP1L1/PDGFRα To Induce Mastocytosis in a Chronic Eosinophilic Leukemia Murine Model.

FIP1L1/PDGFRα (F/P) fusion protein has been identified as a cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). Our group has previously described a murine CEL/HES model based on the expression of both F/P and T-cell-dependent overexpression of IL-5 (Yamada Y et al., Blood 2006), which develops a full hypereosinophilic syndrome with eosinophil infiltration into multiple organs similar to that observed in patients with CEL/HES (CEL-like mouse). Patients with F/P⁺ HES/CEL also display mastocytosis. Since mast cell (MC) development largely depends on c-kit signaling induced by its ligand SCF, we aimed to determine if SCF collaborates with the F/P fusion protein and IL-5 to enhance MC development. The CEL-like mice showed higher levels of MC infiltration in small intestine compared to transplanted mice with IL-5 transgenic HSC/P (control, Table 1). Interestingly, the intestinal MC infiltration of CEL-like mice was primarily associated with MC residing in the lamina propria and intraepithelial locations associated with villi; whereas MC in control mice were primarily in the crypt areas (47-fold higher mast cell levels in villi compared to those of control mice). In addition to the small intestine, skin MC infiltration was also significantly increased in CEL-like mice (Table 1). Notably, F/P⁺ BM hematopoietic stem cell/progenitor (HSC/P) showed proliferation and MC differentiation in vitro in the absence of cytokines (2.3-fold cell expansion, 54% c-kit⁺/FcεRIα⁺ cells) while empty vector (EGFP alone)-transduced (control) HSC/P did not survive in this culture condition. Such an expansion became even higher (36-fold expansion, 90% c-kit⁺/FcεRIα⁺ cells and 2,000-fold higher than control HSC/P) in the presence of low-concentration of SCF (10 ng/ml) for 3 weeks in culture. In contrast, culture with no cytokines or low-dose of SCF did not induce any MC development from control HSC/P. Unlike low-concentration of SCF, IL-3 (100 ng/ml), which induces a rapid and significant MC expansion in control cells, impaired MC development of F/P⁺ HSC/P (129-fold lower expansion at 3 weeks of culture), suggesting that MC proliferation induced by F/P expression may trigger different signaling pathways than during normal MC differentiation induced by IL-3. In summary, the F/P fusion protein induces murine mastocytosis via SCF/c-kit signaling, which is synergistically enhanced by IL-5 overexpression.