Protein ISG15 Modification in the Development and the Treatment of Chronic Myeloid Leukemia; Final rept. 1 Jun 2003-31 May 2007

摘要

Interferons are useful drugs in treating chronic myeloid leukemia (CML). One of the cellular responses of interferon treatment is the activation of protein modification by ISG15. We have cloned a novel gene encoding a protease UBP43 that specifically removes ISG15 from ISG15 modified proteins. Furthermore, we have generated UBP43 knockout mice. UBP43 deficient hematopoietic cells have much higher levels of ISG15 modified proteins upon interferon stimulation and are hypersensitive to interferon treatment. This grant is to demonstrate that protein ISG15 modification is crucial for interferon function in CML treatment and to analyze the effect of UBP43 on CML development. In the past funding period, we have characterized BCR-ABL positive leukemia cell lines that have higher than normal or lower than normal levels of ISG15 conjugation. Furthermore, we have completed the studies on UBP43 knockout mice in the resistance to BCR/ABL induced CML development and demonstrated that interferon plays a critical role in the process. One important finding is that the effect of UBP43 in interferon signaling is independent of its function in protein ISGylation.