Three AML cell variants (M/A, M/A* from MOLM-13 and S/A from SKM-1) were established for resistance by the same protocol using 5-azacytidine (AZA) as a selection agent. These AZA-resistant variants differ in their responses to other cytosine nucleoside analogs, including 5-aza-2'-deoxycytidine (DAC), as well as in some molecular features. Differences in global DNA methylation, protein levels of DNA methyltransferases, and phosphorylation of histone H2AX were observed in response to AZA and DAC treatment in these cell variants. This could be due to changes in the expression of uridine-cytidine kinases 1 and 2 (UCK1 and UCK2) demonstrated in our cell variants. In the M/A variant that retained sensitivity to DAC, we detected a homozygous point mutation in UCK2 resulting in an amino acid substitution (L220R) that is likely responsible for AZA resistance. Cells administered AZA treatment can switch to de novo synthesis of pyrimidine nucleotides, which could be blocked by inhibition of dihydroorotate dehydrogenase by teriflunomide (TFN). This is shown by the synergistic effect of AZA and TFN in those variants that were cross-resistant to DAC and did not have a mutation in UCK2.
- Publikační typ
- časopisecké články MeSH
Myelodysplastic syndromes (MDSs) represent clonal hematopoietic stem cell (HSC) disorders in which genetic and/or epigenetic alteration are involved in the normal function of hematopoietic stem and progenitor cells. This results in the development of blood cytopenias and bone marrow dysplasia. In recent years, therapy with hypomethylating agents (HMAs) in combination with supportive therapies is recommended as frontline treatment for patients with high-risk MDSs according to International Prognostic Scoring System (IPSS HR-MDS). Therapy with HMAs is essential namely for IPSS HR-MDS patients who do not proceed to immediate allogeneic stem cell transplantation (al‐ loSCT). For IPSS LR-MDS (International Prognostic Scoring System, low-risk MDSs) patients, however, supportive therapies and growth factors are the mainstay of treatment. Some patients in this group are treated with immunomodulatory agents derived from thalidomide (lenalidomide) or using immunosuppressive therapy (IST). The therapeu‐ tic decisions can change during the course of the disease based on changes in risk- category and the functional status of patients, in response to prior therapies, changes in patient preferences, and other factors. Resistance to chemotherapy is a serious obstacle to the successful treatment of overall malignancies, including AML and MDS. The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR) phenotype. MDR represents the induction of large-scale defensive mechanisms from which the upregulation of membrane transporters (like P-glycoprotein – P-gp) effluxing chemotherapeutic drugs from tumor cells represents the most observed molecular causality. Other mechanisms of MDR include drug metabolism, alterations in drug-induced apoptosis, epigenetic changes, epithelial-mesenchymal transition, alteration in drug targets structures, and acceleration of DNA repair. The present contribution represents a state-of-the-art review of available knowledge about this issue.
