Myelodysplastic syndrome (MDS) with deletion of the long arm of the chromosome 5 (5q - syndrome, del( 5q)) can be characterized by anemia, macrocytosis, a normal or high platelet count, and hypolobulated megakaryocytes in the bone marrow. 5q - syndrome belongs to low - risk MDS, which means low risk to transform to acute myeloid leukemia. 5q - syndrome is ass ociated with female predominance and older age. Another sign is transfusion burden that is treated by erythropoiesis - stimulating agents (ESA) as erythropoietin (EPO). Moreover, the response of MDS patients is around 30 - 60% with the median of the response b eing ~ 24 months. The second line of treatment is lenalidomide (LEN) which is a derivate of teratogenic analog thalidomide. LEN increases erythropoiesis and inhibits the growth of del(5q) erythroid progenitors in vivo and it does not have a significant effe ct on the growth of normal CD34+ progenitors or cytogenetically normal progenitors in MDS with del(5q) clones. LEN is used as therapy in multiple myeloma, myelodysplastic syndrome, and lymphoma. LEN is an expensive agent and not every MDS patient re sponds to this therapy. This is a reason why is a need to find a biomarker for the determination of successful treatment. Some multiple myeloma studies showed that cereblon can be the biomarker...

Nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of NRF1 or NRF2 results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated. Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediates ubiquitylation and degradation of NRF2 through its NRF2-ECH homology-like domain 2 (Neh2). Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and stabilizes it. Consistently, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, whereas NRF2 is dramatically stabilized in KEAP1(-/-) cells. Replacing NRF1's Neh2L domain with NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino acids between the DLG and ETGE motifs, not just the motifs themselves, are essential for KEAP1-mediated degradation. Systematic site-directed mutagenesis identified the core amino acid residues required for KEAP1-mediated degradation and further indicated that the DLG and ETGE motifs with correct spacing are insufficient as a KEAP1 degron. Our results offer critical insights into our understanding of the differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles.

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