Telomeres compose the end portions of human chromosomes, and their main function is to protect the genome. In hematological disorders, telomeres are shortened, predisposing to genetic instability that may cause DNA damage and chromosomal rearrangements, inducing a poor clinical outcome. Studies from 2010 to 2019 were compiled and experimental studies using samples of patients diagnosed with hematological malignancies that reported the size of the telomeres were described. Abnormal telomere shortening is described in cancer, but in hematological neoplasms, telomeres are still shortened even after telomerase reactivation. In this study, we compared the sizes of telomeres in leukemias, myelodysplastic syndrome and lymphomas, identifying that the smallest telomeres are present in patients at relapse. In conclusion, the experimental and clinical data analyzed in this review demonstrate that excessive telomere shortening is present in major hematological malignancies and its analysis and measurement is a crucial step in determining patient prognosis, predicting disease risk and assisting in the decision for targeted therapeutic strategies.The word telomere originates from the Greek words τέλος (telos, end, extremity)+μέρος (meros, part), meaning "part of the extremity". The telomeres compose the end portions of chromosomes and consist of many 5'-TTAGGG-3' noncoding repeats (1).During a normal lifespan, telomeres naturally shorten. However, this can become a problem when excessive telomere shortening is observed in stem cells of both pediatric and adult patients. Healthy cells are predisposed to a division limit, also known as Hayflick limit, of 50 to 70 divisions before the cell undergoes senesce or apoptosis due to telomere attrition (2, 3).Short telomeres are associated with genetic instability, which may characterize them as a predisposition factor for hematological malignancies (4, 5). Human Telomeres and their FunctionsHuman telomeres are the end portions of chromosomes, which act primarily in DNA protection and genomic stability, preventing fusions and damage to the genetic material. Telomeres are composed of approximately 1000 to 2000 base pairs or 5-12 kb of non-coding TTAGGG repeats, which interacts with a group of proteins denominated as Shelterin complex (Figure 1) (3,(6)(7)(8).A major characteristic of telomeres is their progressive shortening that happens naturally with each division of somatic cells. The shortening occurs due to the DNA end replication problem, which consists of the inability of the cellular machinery to effectively synthesize the chromosomes ends during replication, alongside with the lack or insufficiency of pathways that promote telomere elongation, such as telomerase activity or the alternative lengthening of telomeres (ALT) (9-11).Telomere elongation occurs primarily by human telomerase (hTERT) activity, which is a ribonucleoprotein enzyme specialized in neutralizing telomeric DNA attrition by synthesizing new TTAGGG repeats at chromosome ends. This enzyme is composed by two subunits...
Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.
The idea of utilizing poly-ADP-ribose polymerase inhibitors (PARPi) as therapeutics for cancer has grown in popularity since its original approval for clinical usage in treatment of BRCA DNA repair-associated-mutated ovarian cancer. In this study, we evaluated experimental data regarding in vitro studies utilizing PARPi as a treatment for tyrosine kinase (TK)-dependent leukemia. Studies from 2015 to 2019 were compiled and the ones with most relevant TK pathways and PARP inhibition were analyzed. PARPi showed activity against many leukemia cell lines and samples from patients with primary leukemia, especially when combined with other signaling pathway inhibitor drugs, improving upon the hypothesis that the utilization of PARPi has potential as a new therapeutic approach in treatment of primary leukemia and TK-dependent leukemia.
Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.
Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients’ samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-β, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs’ roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.
Direitos para esta edição cedidos à Atena Editora pelos autores. Todo o conteúdo deste livro está licenciado sob uma Licença de Atribuição Creative Commons. Atribuição-Não-Comercial-NãoDerivativos 4.0 Internacional (CC BY-NC-ND 4.0). O conteúdo dos artigos e seus dados em sua forma, correção e confiabilidade são de responsabilidade exclusiva dos autores, inclusive não representam necessariamente a posição oficial da Atena Editora. Permitido o download da obra e o compartilhamento desde que sejam atribuídos créditos aos autores, mas sem a possibilidade de alterá-la de nenhuma forma ou utilizá-la para fins comerciais. Todos os manuscritos foram previamente submetidos à avaliação cega pelos pares, membros do Conselho Editorial desta Editora, tendo sido aprovados para a publicação com base em critérios de neutralidade e imparcialidade acadêmica. A Atena Editora é comprometida em garantir a integridade editorial em todas as etapas do processo de publicação, evitando plágio, dados ou resultados fraudulentos e impedindo que interesses financeiros comprometam os padrões éticos da publicação. Situações suspeitas de má conduta científica serão investigadas sob o mais alto padrão de rigor acadêmico e ético.
The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.