Roles and Regulation of BCL-xL in Hematological Malignancies.

Members of the Bcl-2 family are proteins that play an essential role in the regulation of apoptosis, a crucial process in development and normal physiology in multicellular organisms. The essential mechanism of this family of proteins is given by the role of pro-survival proteins, which inhibit apoptosis by their direct binding with their counterpart, the effector proteins of apoptosis. This family of proteins was named after the typical member Bcl-2, which was named for its discovery and abnormal expression in B-cell lymphomas. Subsequently, the structure of one of its members BCL-xL was described, which allowed one to understand much of the molecular mechanism of this family. Due to its role of BCL-xL in the regulation of cell survival and proliferation, it has been of great interest in its study. Due to this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that BCL-xL can or cannot play a role in cancer depending on the cellular or tissue context. This review discusses recent advances in its transcriptional regulation of BCL-xL, as well as the advances regarding the activities of BCL-xL in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.

Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

The essential roles of small non-coding RNAs and RNA modifications in normal and malignant hematopoiesis.

Hematopoietic stem cells (HSCs) developing from mesoderm during embryogenesis are important for the blood circulatory system and immune system. Many factors such as genetic factors, chemical exposure, physical radiation, and viral infection, can lead to the dysfunction of HSCs. Hematological malignancies (involving leukemia, lymphoma, and myeloma) were diagnosed in more than 1.3 million people globally in 2021, taking up 7% of total newly-diagnosed cancer patients. Although many treatments like chemotherapy, bone marrow transplantation, and stem cell transplantation have been applied in clinical therapeutics, the average 5-year survival rate for leukemia, lymphoma, and myeloma is about 65%, 72%, and 54% respectively. Small non-coding RNAs play key roles in a variety of biological processes, including cell division and proliferation, immunological response and cell death. With the development of technologies in high-throughput sequencing and bioinformatic analysis, there is emerging research about modifications on small non-coding RNAs, as well as their functions in hematopoiesis and related diseases. In this study, we summarize the updated information of small non-coding RNAs and RNA modifications in normal and malignant hematopoiesis, which sheds lights into the future application of HSCs into the treatment of blood diseases.

Tixagevimab/Cilgavimab as pre-exposure prophylaxis against SARS-CoV-2 in patients with hematological malignancies.

The approved combination of Tixagevimab/Cilgavimab has been shown to decrease the rate of symptomatic SARS-CoV-2 infection in patients at increased risk of inadequate response to vaccination. However, Tixagevimab/Cilgavimab was tested in a few studies that included patients with hematological malignancies, even if this population has shown an increased risk of unfavorable outcomes following infection (with high rates of hospitalization, intensive care unit admission, and mortality) and poor significant immunization following vaccines. We performed a real-life prospective cohort study to evaluate the rate of SARS-CoV-2 infection following pre-exposure prophylaxis with Tixagevimab/Cilgavimab in anti-spike seronegative patients compared to a cohort of seropositive patients who were observed or received a fourth vaccine dose. We recruited 103 patients with a mean age of 67 years: 35 (34%) received Tixagevimab/Cilgavimab and were followed from March 17, 2022, until November 15, 2022. After a median follow-up of 4.24 months, the 3-month cumulative incidence of infection was 20% versus 12% in the Tixagevimab/Cilgavimab and observation/vaccine groups respectively (HR 1.57; 95% CI: 0.65-3.56; p = 0.34). In this study, we report our experience with Tixagevimab/Cilgavimab and a tailored approach to SARS-CoV-2 infection prevention in patients with hematological malignancies during the SARS-CoV-2 omicron surge.

Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review.

Introduction: Patients with hematological malignancies (HMs), like chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), have a high risk of secondary immunodeficiency (SID), SID-related infections, and mortality. Here, we report the results of a systematic literature review on the potential association of various cancer regimens with infection rates, neutropenia, lymphocytopenia, or hypogammaglobulinemia, indicative of SID. Methods: A systematic literature search was performed in 03/2022 using PubMed to search for clinical trials that mentioned in the title and/or abstract selected cancer (CLL, MM, or NHL) treatments covering 12 classes of drugs, including B-lineage monoclonal antibodies, CAR T therapies, proteasome inhibitors, kinase inhibitors, immunomodulators, antimetabolites, anti-tumor antibiotics, alkylating agents, Bcl-2 antagonists, histone deacetylase inhibitors, vinca alkaloids, and selective inhibitors of nuclear export. To be included, a publication had to report at least one of the following: percentages of patients with any grade and/or grade ≥3 infections, any grade and/or grade ≥3 neutropenia, or hypogammaglobulinemia. From the relevant publications, the percentages of patients with lymphocytopenia and specific types of infection (fungal, viral, bacterial, respiratory [upper or lower respiratory tract], bronchitis, pneumonia, urinary tract infection, skin, gastrointestinal, and sepsis) were collected. Results: Of 89 relevant studies, 17, 38, and 34 included patients with CLL, MM, and NHL, respectively. In CLL, MM, and NHL, any grade infections were seen in 51.3%, 35.9% and 31.1% of patients, and any grade neutropenia in 36.3%, 36.4%, and 35.4% of patients, respectively. The highest proportion of patients with grade ≥3 infections across classes of drugs were: 41.0% in patients with MM treated with a B-lineage monoclonal antibody combination; and 29.9% and 38.0% of patients with CLL and NHL treated with a kinase inhibitor combination, respectively. In the limited studies, the mean percentage of patients with lymphocytopenia was 1.9%, 11.9%, and 38.6% in CLL, MM, and NHL, respectively. Two studies reported the proportion of patients with hypogammaglobulinemia: 0-15.3% in CLL and 5.9% in NHL (no studies reported hypogammaglobulinemia in MM). Conclusion: This review highlights cancer treatments contributing to infections and neutropenia, potentially related to SID, and shows underreporting of hypogammaglobulinemia and lymphocytopenia before and during HM therapies.

KLF4 inhibition by Kenpaullone induces cytotoxicity and chemo sensitization in B-NHL cell lines via YY1 independent.

Krüppel-like factor 4 (KLF4) is a member of the KLF transcription factor family containing zinc-fingers, and is involved in the regulation of apoptosis, proliferation and differentiation of B cells and B-cell malignancies. KLF4 can act like an oncogene, we shown that KLF4 overexpression correlated with poor prognostic and chemoresistance in B-NHL. In addition, we shown that KLF4 is regulated by YY1. In this study, we demonstrate that chemical inhibition of KLF4 by Kenpaullone, results in suppression of proliferation, cell survival, downregulation of Bcl-2 and increases apoptosis in B-NHL cell lines through YY1 independent pathway. Combination of Kenpaullone and Doxorubicin, increased apoptosis. The co-expressions of KLF4/YY1 or KLF4/Bcl-2 in NHL was analyzed using Oncomine Database, exhibiting a positive correlation of expression. The present findings suggest that the chemical inhibition of KLF4 by Kenpaullone treatment could be a potential therapeutic alternatively in KLF4+ lymphomas.

Function of Deptor and its roles in hematological malignancies.

Deptor is a protein that interacts with mTOR and that belongs to the mTORC1 and mTORC2 complexes. Deptor is capable of inhibiting the kinase activity of mTOR. It is well known that the mTOR pathway is involved in various signaling pathways that are involved with various biological processes such as cell growth, apoptosis, autophagy, and the ER stress response. Therefore, Deptor, being a natural inhibitor of mTOR, has become very important in its study. Because of this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that Deptor can act as an oncogene or tumor suppressor depending on the cellular or tissue context. This review discusses recent advances in its transcriptional and post-transcriptional regulation of Deptor. As well as the advances regarding the activities of Deptor in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.

Fecal Microbiota Transplant Mitigates Adverse Outcomes Seen in Patients Colonized With Multidrug-Resistant Organisms Undergoing Allogeneic Hematopoietic Cell Transplantation.

The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT). This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant differences and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis between both groups to non-MDRO colonized control cohorts (2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4% versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than their paired non-MDRO-colonized cohort. Conversely, there was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2% respectively, p=0.24) between the FMT-MDRO group and their paired non-MDRO cohort. Collectively, these data suggest that negative clinical outcomes, including mortality associated with MDRO colonization, may be ameliorated by pre-HCT FMT, even in the absence of intestinal MDRO decolonization. Further work is needed to explore this observed benefit.

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns.

DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function mutations in DNA damage repair genes. DNA repair syndromes with biallelic disturbance of essential DNA damage response pathways manifest early in life with multi-systemic involvement and a high propensity for hematologic and solid cancers, as well as bone marrow failure. In this review, we describe classic biallelic DNA repair cancer syndromes arising from faulty single- and double-strand DNA break repair, as well as dysfunctional DNA helicases. These clinical entities include xeroderma pigmentosum, constitutional mismatch repair deficiency, ataxia telangiectasia, Nijmegen breakage syndrome, deficiencies of DNA ligase IV, NHEJ/Cernunnos, and ERCC6L2, as well as Bloom, Werner, and Rothmund-Thompson syndromes. To give an in-depth understanding of these disorders, we provide historical overview and discuss the interplay between complex biology and heterogeneous clinical manifestations.

MicroRNA-7 Regulates Migration and Chemoresistance in Non-Hodgkin Lymphoma Cells Through Regulation of KLF4 and YY1.

The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.

Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances.

Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events. Continuous investigations regarding the biological importance of each of the BCL-2 family components and the clinical rationale to achieve optimal therapeutic outcomes, using either monotherapy or in combination with other targeted agents, have generated inspiring progress in the field. Genomic, epigenomic and biological analyses including BH3 profiling facilitate effective evaluation of treatment response, cancer recurrence and drug resistance. In this review, we summarize the biological features of each of the components in the BCL-2 apoptotic pathways, analyze the regulatory mechanisms and the pivotal roles of BCL-2 family members in the pathogenesis of major types of hematologic malignances, and evaluate the potential of apoptosis- and BCL-2-targeted strategies as effective approaches in anti-cancer therapies.