New Candidate Genes for Lack of Sensitivity to Therapy in Pediatric Leukemias

Abstract

In the recent years, significant development of molecular genetics has contributed to the better understanding of leukemogenesis and classification of the different leukemia subtypes. Patients diagnosed with acute leukemia usually undergo chemotherapy, which involves the induction of remission, consolidation of remission and maintenance therapy. Patients are still vulnerable to relapse due to differences in the sensitivity of leukemia cells to the chemotherapeutic agent, because of the active drugs removal from the cells, improving the repair of DNA damage or abnormalities in the apoptotic pathway. Cell adhesion and miRNA expression level also affect the drug resistance. New candidate genes and genes correlated with the disease have been sought to increase the survival of patients with leukemia. Candidate gene is usually a loci located in a certain chromosomal region suspected of involvement to the disease course or its expression product regulates disease progression. There are classic and digital methods of finding candidate genes. These techniques are inexpensive, quick and easy to carry out. Unfortunately, due to insufficient knowledge of the disease etiology and low accuracy, researchers cannot detect all genes, involved in leukemogenesis and cell resistance. Currently, scientists have many tools used for selecting genes, such as expression microarrays, comparative genomic hybridization and next generation sequencing. Among the validation techniques for candidate genes, the mostly used ones are fluorescent in situ hybridization and real-time PCR. In our review we present 18 candidate genes of resistance to therapy in childhood leukemia.

Epigenetic analysis reveals significant differential expression of miR‐378C and miR‐128‐2‐5p in a cohort of relapsed pediatric B‐acute lymphoblastic leukemia cases

“…However, many recent studies in acute leukemia cases have shown that miR‐128b is significantly overexpressed in pediatric ALL cases at diagnosis than controls and in ALL cases more than in AML cases 27‐30 . In addition, in vitro studies performed have shown miR‐128b to be involved in development of drug resistance to vincristine and prednisolone, pointing toward a possible mechanism for disease relapse in ALL 31 . miR‐378c is a tumor suppressive miRNA and studies have shown it to be downregulated in cancers especially bladder and colon cancers and its down‐regulation leads to tumor metastasis and poor outcome 32,33 .…”

Advanced technological tools to study multidrug resistance in cancer

“…Regarding MDR, NGS technologies allow us to identify DNA-and RNA-based molecular profiles associated with tumor development, progression and therapy outcome and thus recognize genetic determinants of MDR phenomenon in solid tumors (Chandana et al, 2019;Gov et al, 2017;Kyrochristos et al, 2019;Verma and Sharma, 2018) and leukemia (Albitar et al, 2017;Bereza et al, 2017;Szankasi et al, 2016). On the basis of ultra-deep sequencing, it is also possible to understand and combat the antibiotic resistome (Crofts et al, 2017;Hadjadj et al, 2019) and characterize in detail, drug resistance-associated mutations in pathogens and viruses causing serious diseases (Alidjinou et al, 2017;Gautam et al, 2019;Parker and Chen, 2017;Ramanathan et al, 2017;Soares et al, 2019;Thomson et al, 2016) as summarized in Fig.…”

MiRNA Dysregulation in Childhood Hematological Cancer

“…A study published in 2015 by Hamzeh et al showed that miRNA-related dysregulated pathways were associated to resistance to asparaginase (L_ASP), daunorubicin (DAUNO), prednisolone (PREDS), and vincristine (VIN) [ 36 ]. Several miRNAs have been attributed an association with leukemia treatment resistance, such as miR-34 [ 37 , 38 ], miR-128b, and miR-223 [ 39 ]. Zhang et al [ 23 ] described an miRNA signature (miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633) that was able to predict prednisone (PRED) response in childhood ALL patients.…”