Leukemogenic kinase FIP 1L1‐ PDGFRA and a small ubiquitin‐like modifier E3 ligase, PIAS 1, form a positive cross‐talk through their enzymatic activities

Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP 1L1‐ PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP 1L1‐ PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti‐apoptotic state. Contribution of the N‐terminal FIP 1L1 portion is necessary for FIP 1L1‐ PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS 1 as a FIP 1L1‐ PDGFRA association molecule by yeast two‐hybrid screening. Our analyses indicate that the FIP 1L1 portion of FIP 1L1‐ PDGFRA is required for efficient association with PIAS 1. As a consequence of the association, FIP 1L1‐ PDGFRA phosphorylates PIAS 1. Moreover, the kinase activity of FIP 1L1‐ PDGFRA stabilizes PIAS 1. Therefore, PIAS 1 is one of the downstream targets of FIP 1L1‐ PDGFRA . Moreover, we found that PIAS 1, as a SUMO E3 ligase, sumoylates and stabilizes FIP 1L1‐ PDGFRA . In addition, suppression of PIAS 1 activity by a knockdown experiment resulted in destabilization of FIP 1L1‐ PDGFRA . Therefore, FIP 1L1‐ PDGFRA and PIAS 1 form a positive cross‐talk through their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1‐activating enzyme, also destabilizes FIP 1L1‐ PDGFRA , and while the tyrosine kinase inhibitor imatinib suppresses FIP 1L1‐ PDGFRA ‐dependent cell growth, ginkgolic acid or si RNA of PIAS 1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS 1 is a potential target in the treatment of FIP 1L1‐ PDGFRA ‐positive chronic eosinophilic leukemia.