Abstract
Large HERC E3 ubiquitin ligase family members, HERC1 and HERC2, are staggeringly complex proteins that can intervene in a wide range of biological processes, such as cell proliferation, DNA repair, neurodevelopment, and inflammation. Therefore, mutations or dysregulation of large HERCs is associated with neurological disorders, DNA repair defects, and cancer. Though their role in solid tumors started to be investigated some years ago, our knowledge about HERCs in non-solid neoplasm is greatly lagging behind. Chronic Myeloid Leukemia (CML) is a model onco-hematological disorder because of its unique and unambiguous relation between genotype and phenotype due to a single genetic alteration. In the present study, we ascertained that the presence of the BCR-ABL fusion gene was inversely associated with the expression of the HERC1 and HERC2 genes. Upon the achievement of remission, both HERC1 and HERC2 mRNAs raised again to levels comparable to those of the healthy donors. Additionally, our survey unveiled that their gene expression is sensitive to different Tyrosine Kinases Inhibitors (TKIs) in a time-dependent fashion. Interestingly, for the first time, we also observed a differential HERC1 expression when the leukemic cell lines were induced to differentiate towards different lineages revealing that HERC1 protein expression is associated with the differentiation process in a lineage-specific manner. Taken together, our findings suggest that HERC1 might act as a novel potential player in blood cell differentiation. Overall, we believe that our results are beneficial to initiate exploring the role/s of large HERCs in non-solid neoplasms.
Highlights
Introduction published maps and institutional affilTo some extent, Chronic Myeloid Leukemia (CML) can be considered a model disease in the onco-hematology field but more broadly in oncology
The present retrospective study was carried out on 29 CML patients under tyrosine kinase inhibitors (TKIs) therapy, and all of them were positive for the p210 BCR-ABL rearrangement at diagnosis
In acute lymphoblastic leukemia, somatic deletions of HERC1 were associated with lower levels of the protein MSH2, which is in turn involved in DNA mismatch repair [29], and mutations in HERC1 were found in T-ALL patients [30]
Summary
Chronic Myeloid Leukemia (CML) can be considered a model disease in the onco-hematology field but more broadly in oncology. It is a clonal myeloproliferative disorder characterized by a single genetic alteration affecting the hematopoietic stem cells. The balanced reciprocal translocation t(9;22) (q34;q11) gives rise to a constitutively active tyrosine kinase oncoprotein, BCR-ABL, that is the causative and functional lesion of CML. The CML can be effectively treated by selectively targeting BCR-ABL with small molecules tyrosine kinase inhibitors (TKIs), which by inhibiting the kinase activity, drive the cells towards apoptosis. The first tyrosine kinase inhibitor (TKI) developed and successfully used in the clinic was Imatinib [3,4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
