Chronic myeloid leukemia, tyrosine kinase inhibitors and cardiovascular system.

OBJECTIVE: Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. MATERIALS AND METHODS: Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. RESULTS: Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. CONCLUSIONS: The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

Hematological aspects of the COVID-19 syndrome.

OBJECTIVE: Viral infections could complicate hematopoiesis and, in some cases, they may worsen the clinical prognosis of blood disorders. SARS-CoV-2 and COVID-19, as a viral disease, can have serious impact on the disease course of hematological neoplastic diseases and can cause hematological complications. The aim of this paper is to review the hematologic aspects of COVID-19 syndrome and the potential management options for SARS-CoV-2 including the convalescent plasma, hemostatic agents and proper anticoagulant treatment. MATERIALS AND METHODS: Up to February 2022, literature searches were performed using the internet search engines MEDLINE and EMBASE: (i) COVID-19; (ii) Hematology. PRISMA flow diagram described the COVID-19 and hematology search. RESULTS: According to our COVID-19 and hematology research on research databases, we included 82 studies in the current paper. The issues of the impact of the COVID-19 pandemic on hematological diseases, the role of t-lymphocytes in donor lymphocyte infusion and viruses, hemato-immunologic research in COVID-19, local bone marrow renin-angiotensin system and viral infections, clinical management of COVID-19 infection via hemostatic agents, immune plasma treatment of COVID-19, anticoagulant treatment of COVID-19 associated thrombosis are comprehensively described in this paper. CONCLUSIONS: The final episode of this pandemic will include the "chimerism-mediated immunotherapy" that will eventually lead to end of the COVID-19 process. The recent Omicron variant seems to have unique evasion effects on the interferon gene expression which will boost the chimerism-mediated immunotherapy without high mortality rates.

Three critical clinicobiological phases of the human SARS-associated coronavirus infections.

OBJECTIVE: COVID-19 immune syndrome is a multi-systemic disorder induced by the COVID-19 infection. Pathobiological transitions and clinical stages of the COVID-19 syndrome following the attack of SARS-CoV-2 on the human body have not been fully explored. The aim of this review is to outline the three critical prominent phase regarding the clinicogenomics course of the COVID-19 immune syndrome. MATERIALS AND METHODS: In the clinical setting, the COVID-19 process presents as "asymptomatic/pre-symptomatic phase", "respiratory phase with mild/moderate/severe symptoms" and "multi-systemic clinical syndrome with impaired/disproportionate and/or defective immunity". The corresponding three genomic phases include the "ACE2, ANPEP transcripts in the initial phase", "EGFR and IGF2R transcripts in the propagating phase" and the "immune system related critical gene involvements of the complicating phase". RESULTS: The separation of the phases is important since the genomic features of each phase are different from each other and these different mechanisms lead to distinct clinical multi-systemic features. Comprehensive genomic profiling with next generation sequencing may play an important role in defining and clarifying these three unique separate phases for COVID-19. From our point of view, it is important to understand these unique phases of the syndrome in order to approach a COVID-19 patient bedside. CONCLUSIONS: This three-phase approach may be useful for future studies which will focus on the clinical management and development of the vaccines and/or specific drugs targeting the COVID-19 processes. ANPEP gene pathway may have a potential for the vaccine development. Regarding the specific disease treatments, MAS agonists, TXA127, Angiotensin (1-7) and soluble ACE2 could have therapeutic potential for the COVID-19 course. Moreover, future CRISPR technology can be utilized for the genomic editing and future management of the clinical course of the syndrome.

Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies.

The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules.