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Acute lymphoblastic leukemia (ALL) has been established as the most common acute leukemia in children, accounting for 80–85% of cases. ALL occurs mostly in children and it is considered as a high-risk disease in the elderlies. ALL is characterized by a clonal disorder where the normal hematopoiesis is replaced by a malignant clonal expansion of lymphoid progenitors. Although many therapeutic strategies have been established to treat ALL leading to improved survival rates, the short-term and long-term complications derived from treatment toxicity represent a critical risk for patients. The treatment-related toxicity suggests a need for the development of new therapy strategies to effectively treat high-risk and low-risk disease. Nowadays, an important approach is focused on the identification of molecules involved in the mechanisms that lead to leukemia generation and progression to determine potential targets at the transcriptional level. MicroRNAs (miRNAs) are a group of key molecules that regulate signaling pathways related to lymphopoiesis. miRNAs participate in the regulation of hematopoietic differentiation and proliferation, as well as their activity. The present review details the recompilation of evidences about the relation between miRNAs and lymphopoiesis, ALL development and progression in order to propose and explore novel strategies to modulate ALL-related miRNA levels as a therapeutic approach.

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Background and Objectives: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. The majority of patients respond to treatment, but those with resistant phenotypes suffer relapse or death. The antifolate methotrexate (MTX) is the most commonly used drug against ALL due to its efficacy. Once inside leukemic cells, MTX is metabolized into methotrexate polyglutamates (MTX-PG) by action of the enzyme folylpolyglutamate synthetase (FPGS), leading to a longer action compared to that of MTX alone. Materials and Methods: In this work, we demonstrated that the combination treatment of methotrexate and 5 and 10 mM glutamic acid could enhance methotrexate cytotoxicity in CCRF-SB (B-ALL) cells. In addition, MTX plus 20 mM glutamic acid was able to improve the synthesis of MTX-PG5. Results: All treatments induced an increase in FPGS expression compared to that of the control group. Furthermore, we detected different cellular expression patterns of FPGS in the different treatments. Conclusion: Based on these findings, we demonstrated that levels of methotrexate polyglutamates (MTX-PGs) could be a key determinant of methotrexate-induced cytotoxicity in CCRF-SB acute lymphoblastic leukemia cells.