Search

Defeating cancer as leukemia has been an up and down challenge. However, leukemia must be treated from the roots. Nowadays, the CRISPR-Cas9 system provided scientists the ability to manipulate the genetic information to correct mutations, rewrite genetic code, or edit immune cells for immunotherapy purposes. Additionally, such system is used for basic and clinical approaches in leukemia therapy. Lymphoid cancers including acute lymphoblastic leukemia (ALL) can be treated by performing gene editing or enhancing immune system through CART cells. Here, we present and detail therapeutic applications of the CRISPR/Cas9 system for immune cell therapy, and knock-out or knock-in of main genes promoting leukemogenesis or ALL progression. We also described current and future challenges, and optimization for the application of CRISPR/Cas9 system to treat lymphoid malignancies.

Las universidades buscan caracterizar a sus estudiantes para prevenir que abandonen la escuela y así, posibilitar su egreso. Entre las variables que se diagnostican y se relacionan con el rendimiento, éxito y trayectoria escolar, están las cognoscitivo-motivacionales: autoestima, autoconcepto y motivación (Pool-Cibrián, Martínez-Guerrero, 2013). Estas variables se construyen a partir de otra: el estilo atribucional, o cómo define la forma en que la persona interpreta lo que le sucede; el académico se refiere a la manera en que un estudiante interpreta lo bueno y lo malo que le ocurre en la escuela o en relación con su aprendizaje (Petri, Govern, 2015). El objetivo del presente estudio fue adaptar el Cuestionario de Estilo Atribucional Académico ( CEAA ), en una población de estudiantes preuniversitarios. El instrumento se adaptó y aplicó a aspirantes para el ingreso a una universidad de la Ciudad de México. En los resultados se observó que los reactivos del cuestionario se organizaron en cuatro factores, de forma coincidente con la propuesta de Peterson et al. (1982), fundamento empírico del instrumento. Se encontró que los factores cuentan con un alpha de Cronbach a>0.75. En futuras investigaciones se podría probar su validez concurrente, comprobar otros modelos factoriales y determinar su validez predictiva respecto del rendimiento escolar.

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.

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

The excess of many chemical substances in humans, such as copper has been reported to induce DNA damage and trigger cancer development...

T cell acute lymphoblastic leukaemia is a type of cancer that develops from lymphoid progenitors, and chemotherapy is corner stone of the treatment. Thiopurine drugs, consisting of 6-mercaptopurine, 6-thioguanine, and azathioprine (Aza), can effectively treat this disease. To be activated, Aza must first be biotransformed to 6-mercaptopurine by thiol groups in glutathione. However, glutathione is decreased in cancer cells due to high levels of reactive oxygen species (ROS). N-acetylcysteine could provide thiol groups for glutathione synthesis to biotransform Aza. Using flow cytometry, the ability of N-acetylcysteine to increase the antiproliferative and apoptotic effects of Aza without increasing ROS was tested in Jurkat cells. Individually, Aza 1.0 and 2.0 μM, as well as N- acetylcysteine 3.0 mM, induced apoptosis and cell cycle arrest. Together, Aza + N-acetylcysteine significantly reduced proliferation compared to that obtained with the individual drugs. Combination of N-acetylcysteine 3.0 mM with Aza 1.0 μM was as effective at inducing apoptosis as Aza 2.0 μM alone. The combination of N-acetylcysteine 3.0 mM + Aza 1.0 μM increased cell cycle arrest at the G2/M phase. We found that Aza 1.0 or 2.0 μM induced a significant increase in ROS compared to that in untreated cells, while N-acetylcysteine 3.0 mM and N-acetylcysteine 3.0 mM + Aza 1.0 μM kept ROS at control levels; the latter drugpairing represents a favourable combination to reduce oxidative stress in the presence of Aza. In conclusion, N-acetylcysteine augments antiproliferative and apoptotic effects of Aza without increasing ROS in vitro.

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.

La leucemia linfoblástica aguda T (LLA-T) es un tipo de cáncer derivado del linaje linfoide, y presenta un mal pronóstico al ser quimiorresisente. El tratamiento de elección es la quimioterapia y los fármacos que presentan mayor eficacia son las tiopurinas. La Azatioprina (Aza) es la tiopurina más tóxica, debido a que se utiliza mayor dosis ya que necesita ser biotransformada por grupos sulfhidrilo (SH) presentes en el glutatión o la cisteína cuya biodisponibilidad, en células cancerosas, está disminuida al contener niveles de especies reactivas de oxígeno (ROS) elevadas. Por otro lado, las ROS provocan la oxidación de las tiopurinas y de sus metabolitos activos, disminuyendo así, su efecto quimioterapéutico. La Nacetilcisteína (NAC) es un antioxidante aprobado por la FDA, que podría incrementar la biotransformación de Aza al aportar grupos SH, favorecer la resíntesis de glutatión y disminuir ROS. En este trabajo se utilizó a la par, Aza y NAC en células Jurkat de LLA-T, para favorecer un incremento del efecto antiproliferativo y apoptótico sin incrementar los niveles de ROS. De manera individual, tanto Aza 1.0 y 2.0¿M como NAC 3.0mM indujeron apoptosis y arresto en el ciclo celular. Al utilizar Aza 1.0¿M+ NAC 3.0mM de manera conjunta se obtuvo un efecto antiproliferativo significativamente mayor (p0.05). La combinación de Aza 1.0¿M + NAC 3.0mM incrementaron el arresto del ciclo celular en la fase G2/M; evento favorable para que las células entren en proceso de apoptosis. Aza 1.0 y 2.0¿M indujo un incremento significativamente mayor (p 0.05). The combination of NAC 3.0mM + 1.0¿M Aza increased cell cycle arrest at the G2/M phase; favorable to enter cells undergoing apoptosis event. Aza 1.0 and 2.0¿M induced a significantly greater increase (p