Abstract
Acute myeloid leukemia (AML), the most common form of an acute leukemia, is a malignant disorder of stem cell precursors of the myeloid lineage. Ubiquitination is one of the post-translational modifications (PTMs), and the ubiquitin-like proteins (Ubls; SUMO, NEDD8, and ISG15) play a critical role in various cellular processes, including autophagy, cell-cycle control, DNA repair, signal transduction, and transcription. Also, the importance of Ubls in AML is increasing, with the growing research defining the effect of Ubls in AML. Numerous studies have actively reported that AML-related mutated proteins are linked to Ub and Ubls. The current review discusses the roles of proteins associated with protein ubiquitination, modifications by Ubls in AML, and substrates that can be applied for therapeutic targets in AML.
Highlights
The three most common gene mutations found in Acute myeloid leukemia (AML) are FMS-like tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), and DNA methyltransferase 3α (DNMT3α)
Ubiquitin-Specific Peptidase 28 (USP28) does not bind directly with uridine-cytidine kinase 1 (UCK1), but binds via Kelch like family member 2 (KLHL2) [127]. These data indicate that USP28 decreases the 50 -AZA sensitivity by deubiquitinating and stabilizing the UCK1. These deubiquitinating enzymes (DUBs) are associated with the pathogenesis of the AML (Table 4), which is involved in drug resistance, proliferation, and differentiation
Non-covalent interactions of small ubiquitin-like modifier (SUMO) with substrates are mediated by amino acid sequences termed SUMO-interacting motifs (SIMs) that have been identified in numerous proteins including SUMO E3 [135]
Summary
Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem cells, and the most common form of an acute leukemia It is characterized by clonal expansion of abnormally differentiated blasts of the myeloid lineage in adolescents and the young adult population, having an increasing incidence with advancing age [1,2,3]. The three most common gene mutations found in AML are FMS-like tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), and DNA methyltransferase 3α (DNMT3α). The FLT3 mutations occur in approximately 30% of all AML cases and are a poor prognostic factor for the patients [7]. C/EBPα is a transcription factor that plays an important role in the lineage-specific myeloid differentiation, and C/EBPα mutations occur in ~10% AML cases [17]
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