The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

Abstract

HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs in this context remains unexplored. In the present study we examined the expression of the large HECT E3 Ubiquitin Ligase, HERC1, in blood disorders. Our findings revealed that HERC1 gene expression was severely downregulated both in acute and in chronic myelogenous leukemia at diagnosis, while it is restored after complete remission achievement. Instead, in Philadelphia the negative myeloproliferative neoplasm HERC1 level was peculiarly controlled, being very low in Primary Myelofibrosis and significantly upregulated in those Essential Thrombocytemia specimens harboring the mutation in the calreticulin gene. Remarkably, in CML cells HERC1 mRNA level was associated with the BCR-ABL1 kinase activity and the HERC1 protein physically interacted with BCR-ABL1. Furthermore, we found that HERC1 was directly tyrosine phosphorylated by the ABL kinase. Overall and for the first time, we provide original evidence on the potential tumor-suppressing or -promoting properties, depending on the context, of HERC1 in myeloid related blood disorders.

The Downregulation of Both Giant HERCs, HERC1 and HERC2, Is an Unambiguous Feature of Chronic Myeloid Leukemia, and HERC1 Levels Are Associated with Leukemic Cell Differentiation

“…However, their role in nonsolid tumors has started to be explored quite recently. In our previous study, we reported an association of HERC1 gene expression with some myeloid-related disorders [20]. Curiously, besides our findings, the knowledge regarding the other large HERC sub-family member, HERC2, is currently missing in blood malignancies.…”

“…Overall, it is likely that BCR-ABL exerts a negative effect on the accumulation of these HERC genes. Recently, we observed that BCR-ABL interacts with HERC1 and that the latter is a substrate of the former [20]. Determining the molecular mechanism/s by which large HERCs are downregulated in CML and ascertaining to what levels the aberrant HERCs transcripts dysregulation occurs will be a matter of future studies.…”

“…Several ubiquitin ligases are mutated, overexpressed, or deleted in hematologic malignancies contributing to the pathogenesis of the diseases through accumulation, or excessive degradation, of their substrates which perform critical functions that regulate hematopoietic cell growth and differentiation [15,18,19]. Recently, it has been reported by our group that the HERC1 gene expression dysregulation and some myeloid-related disorders and the physical interaction between BCR-ABL1 and HERC1 [20]. HERC1, together with HERC2, are giant E3 ubiquitin ligases with a molecular weight exceeding 500 kDa.…”

Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies

“…In addition, though very rare, an atypical HERC1-PML transcript fusion mRNA has been described in APL, though the functional outcome of this chimera has not been yet investigated [ 93 ]. Ali and collaborators [ 94 ] have recently reported that HERC1 expression is dysregulated in myeloid related neoplasms. At diagnosis, HERC1 transcript levels are markedly down-regulated in AML, CML and primary myelofibrosis, an aggressive form of myeloproliferative neoplasm (MPN), relatively to bone marrow and peripheral blood control cells.…”

“…MPNs include polycythemia vera, essential thrombocythemia, and primary (idiopathic) myelofibrosis. MPN patients can spontaneously transform into either myelodysplastic syndrome or AML Somatic mutations (JAK2, calreticulin, thrombopoietin receptor 2,17 HERC1 [ 94 ] …”