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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.

cancer science

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