L-Asparaginase e perspectivas no tratamento da leucemia linfoblástica aguda: revisão de literatura / L-Asparaginase and perspectives in the treatment of leukemia acute lymphoblastic: literature review

Introdução: A L-asparaginase tem sido estudada como alternativa no tratamento da Leucemia Linfoblástica Aguda (LLA) uma vez que possui a capacidade de induzir apoptose em células leucêmicas sem causar danos às células normais. Estudos mostraram benefícios no tratamento da LLA, porém com o risco de desenvolver efeitos adversos. Objetivo: Este trabalho visa apresentar e explicar o histórico da L-asparaginase, desafios enfrentados pelo Brasil, mecanismos de ação que envolvem as formas da enzima e efeitos adversos de sua utilização. Métodos: Foram incluídos neste trabalho 54 artigos na língua portuguesa e inglesa consultados em bancos de artigos como PubMed e SciELO, entre o período de 1953 até 2021. Resultados: A L-asparaginase é uma enzima que converte asparagina em aspartato e amônia, isolada a partir de colônias de Escherichia coli e de Erwinia chrysanthemi, além disso foi polimerizada com polietilenoglicol. O uso de corticosteroides, anti-histamínicos e suplementação vitamínica se mostraram eficientes para amenizar os efeitos adversos. Conclusões: É necessário evitar um desabastecimento de L-Asparaginase no Brasil, principalmente por conta da dificuldade de comercialização e alto custo, mesmo sendo um medicamento presente na lista da Organização Mundial da Saúde, considerado essencial.

Introduction: L-asparaginase has been studied as an alternative in the treatment of Acute Lymphoblastic Leukemia (ALL) since it has the ability to induce apoptosis in leukemic cells without causing damage to normal cells. Studies have shown benefits in the treatment of ALL, but with the risk of developing adverse effects. Objective: This work aims to present and explain the history of L-asparaginase, challenges faced by Brazil, mechanisms of action involving the forms of the enzyme and adverse effects of its use. Methods: 54 articles in Portuguese and English were included in this work, consulted in article banks such as PubMed and SciELO, between the period of 1953 to 2021. Results: L-asparaginase is an enzyme that converts asparagine into aspartate and ammonia, isolated from from Escherichia coli and Erwinia chrysanthemi colonies, it was also polymerized with polyethylene glycol. The use of corticosteroids, antihistamines and vitamin supplementation proved to be efficient in mitigating adverse effects. Conclusions: It is necessary to avoid a shortage of L-Asparaginase in Brazil, mainly due to the difficulty of commercialization and high cost, even though it is a drug present on the World Health Organization list, considered essential.

Nbn-Mre11 interaction is required for tumor suppression and genomic integrity.

We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbnmid8 allele was expressed exclusively in hematopoietic lineages (in Nbn-/mid8vav mice). Unlike Nbnflox/floxvav mice with Nbn deficiency in the bone marrow, Nbn-/mid8vav mice were viable. Nbn-/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn-/mid8 mice developed highly penetrant T cell leukemias. Nbn-/mid8vav leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbnmid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn-/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1 We propose that overexpression of MRE11 compensates for the metastable Mre11-Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.

Rejection of leukemic cells requires antigen-specific T cells with high functional avidity.

In a context where injection of antigen (Ag)-specific T cells probably represents the future of leukemia immunotherapy, identification of optimal target Ags is crucial. We therefore sought to discover a reliable marker for selection of the most potent Ags. To this end, (1) we immunized mice against 8 individual Ags: 4 minor histocompatibility Ags (miHAs) and 4 leukemia-associated Ags (LAAs) that were overexpressed on leukemic relative to normal thymocytes; (2) we assessed their ability to reject EL4 leukemic cells; and (3) we correlated the properties of our Ags (and their cognate T cells) with their ability to induce protective antileukemic responses. Overall, individual miHAs instigated more potent antileukemic responses than LAAs. Three features had no influence on the ability of primed T cells to reject leukemic cells: (1) MHC-peptide affinity; (2) the stability of MHC-peptide complexes; and (3) epitope density at the surface of leukemic cells, as assessed using mass spectrometry. The cardinal feature of successful Ags is that they were recognized by high-avidity CD8 T cells that proliferated extensively in vivo. Our work suggests that in vitro evaluation of functional avidity represents the best criterion for selection of Ags, which should be prioritized in clinical trials of leukemia immunotherapy.

The role of estrogen receptor ß in transplacental cancer prevention by indole-3-carbinol.

In the present study, the efficacy of indole-3-carbinol (I3C), a key bioactive component of cruciferous vegetables, for prevention of cancer in offspring exposed in utero to the environmental carcinogen dibenzo[def,p]chrysene (DBC) was evaluated using an estrogen receptor ß (ERß) knockout mouse model. I3C was provided either through the maternal diet coincident with carcinogen exposure during pregnancy or directly to offspring postinitiation with DBC. I3C was effective at reducing T-cell acute lymphoblastic lymphoma/leukemia (T-ALL)-related mortality in offspring only if provided via the maternal diet, although a gender difference in the role of ERß in mediating this response was evident. In female offspring, chemoprevention of T-ALL by maternal dietary I3C required expression of ERß; survival in Esr2 wild-type and heterozygous female offspring was more than 90% compared with 66% in Esr2 null females. Alternatively, ERß status did not significantly impact the transplacental chemoprevention by I3C in males. The possible role of ERß in mediating lung carcinogenesis or chemoprevention by I3C was similarly complicated. Lung tumor incidence was unaltered by either dietary intervention, whereas lung tumor multiplicity was substantially reduced in Esr2 null females on the control diet and marginally lower in Esr2 null males exposed to I3C via the maternal diet compared with their wild-type and heterozygous counterparts. These findings suggest that I3C may act via ERß to prevent or suppress DBC-initiated transplacental carcinogenesis but that the involvement of this receptor seems to differ depending on the cancer type and gender of the offspring.

Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia.

New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic-translation-initiation factor 2 alpha (eIF2α). Inhibition of eIF2α phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2α form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2α by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2α signaling further increased the anti-leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2α in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target.

The Fbw7 and betaTRCP E3 ubiquitin ligases and their roles in tumorigenesis.

The Ubiquitin Proteasome System (UPS) is a major regulator of protein abundance in the cell. The UPS influences the functions of multiple biological processes by targeting key regulators for destruction. E3 ubiquitin ligases are a vital component of the UPS machinery, working with E1 and E2 enzymes to bind substrates and facilitate the transfer of ubiquitin molecules onto the target protein. This poly-ubiquitination, in turn, directs the modified proteins for proteolysis by the 26S proteasome. As the UPS regulates the degradation of multiple oncogenes and tumor suppressors, the dysregulation of this pathway is known to promote various diseases including cancer. While E1 and E2 enzymes have only been minimally linked to cancer development, burgeoning amounts of evidence have implicated loss or gain of E3 function as a key factor in cancer initiation and progression. This review will examine the literature on two SCF-type E3 ligases, SCFFbw7 and SCFbeta-TRCP. In particular, we will highlight novel substrates recently identified for these two E3 ligases, and further discuss how UPS regulation of these targets may promote carcinogenesis.

Precursor T-lymphoblastic lymphoma as a secondary malignancy in a young patient after successful treatment of acute promyelocytic leukemia.

BACKGROUND: Acute promyelocytic leukemia (APL) is a relatively rare subtype of acute myeloid leukemia. It has become the best curable subtype of acute leukemias in adults due to the inclusion of all-trans-retinoic acid (ATRA) in the treatment. Despite the efficacy of ATRA, chemotherapy must be added in APL patients in order to maintain durable complete remission. However, chemotherapy administration is inevitably related to many complications, including the risk of secondary malignancies. T-lymphoblastic lymphoma (T-LBL) is an infrequent disease that belongs to the group of highly aggressive lymphomas. CASE REPORT: The authors describe the case of a 25-year-old woman who was treated for APL in 2002 and developed precursor T-LBL 5 years later. CONCLUSION: Several cases of secondary acute lymphoblastic leukemias in 'cured' APL patients have been described, but probably no patient with secondary precursor T-LBL. Secondary malignancy has become one of the topics discussed (not only) in APL patients. It is apparently related to the excellent treatment outcomes and long-term survival. Better tailored treatment based on relevant prognostic factors allowing chemotherapy reduction or omission in some patients is needed.