Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.

Background: Significant advances have been made in the treatment of chronic lymphocytic leukemia (CLL) since the turn of the new millennium. However, most clinical trials were done in developed countries where minority ethnicities were underrepresented. Materials and Methods: To gauge the quality of research in CLL being done in Pakistan, we conducted a comprehensive literature search using PubMed, Clinicaltrials.gov, and Google Scholar on 14 January 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Results: A total of 16 studies met the inclusion criteria. The most common study design was cross-sectional. Eight studies evaluated the clinicohematological profile of CLL patients and the effect of various cytogenic abnormalities through fluorescence in situ hybridization (FISH) technique on disease progression and prognosis. Five studies discussed the prevalence of abnormalities such as autoimmune cytopenias and other serum chemistry derangements. Only two studies evaluated treatment outcomes, among which one study reported a 2-year overall survival of 65% among patients with 17p deletion. None of the studies had patients on novel targeted agents. No pharmaceutical sponsored or funded clinical trials were found. Conclusions: Our review suggests that although small clinical studies continue to be performed across the country, multiple financial and logistical barriers need to be addressed for larger, more impactful clinical trials to be conducted that will help answer demographic-specific questions and decrease reliance on foreign studies.

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CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy cells, thus presenting itself as a promising therapeutic target. In fact, for many aggressive hematological cancers, including CLL, DLBCL, T-ALL, and NKTL, CD38 expression is significantly associated with poorer prognosis and a hyperproliferative or metastatic phenotype. Studies have shown that, beyond being a biomarker, CD38 functionally mediates dysregulated survival, adhesion, and migration signaling pathways, as well as promotes an immunosuppressive microenvironment conducive for tumors to thrive. Thus, targeting CD38 is a rational approach to overcoming these malignancies. However, clinical trials have surprisingly shown that daratumumab monotherapy has not been very effective in these other blood malignancies. Furthermore, extensive use of daratumumab in MM is giving rise to a subset of patients now refractory to daratumumab treatment. Thus, it is important to consider factors modulating the determinants of response to CD38 targeting across different blood malignancies, encompassing both the transcriptional and post-transcriptional levels so that we can diversify the strategy to enhance daratumumab therapeutic efficacy, which can ultimately improve patient outcomes.

Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field.

In patients with hematologic malignancies due to immune system disorders, especially persistent febrile neutropenia, invasive fungal infections (IFI) occur with high mortality. Aspergillosis, candidiasis, fusariosis, mucormycosis, cryptococcosis and trichosporonosis are the most important infections reported in patients with hematologic malignancies that undergo hematopoietic stem cell transplantation. These infections are caused by opportunistic fungal pathogens that do not cause severe issues in healthy individuals, but in patients with hematologic malignancies lead to disseminated infection with different clinical manifestations. Prophylaxis and creating a safe environment with proper filters and air pressure for patients to avoid contact with the pathogens in the surrounding environment can prevent IFI. Furthermore, due to the absence of specific symptoms in IFI, rapid and accurate diagnosis reduces the mortality rate of these infections and using molecular techniques along with standard mycological methods will improve the diagnosis of disseminated fungal infection in patients with hematologic disorders. Amphotericin B products, extended-spectrum azoles, and echinocandins are the essential drugs to control invasive fungal infections in patients with hematologic malignancies, and according to various conditions of patients, different results of treatment with these drugs have been reported in different studies. On the other hand, drug resistance in recent years has led to therapeutic failures and deaths in patients with blood malignancies, which indicates the need for antifungal susceptibility tests to use appropriate therapies. Life-threatening fungal infections have become more prevalent in patients with hematologic malignancies in recent years due to the emergence of new risk factors, new species, and increased drug resistance. Therefore, in this review, we discuss the different dimensions of the most critical invasive fungal infections in patients with hematologic malignancies and present a list of these infections with different clinical manifestations, treatment, and outcomes.

Circular (circ)RNAs influence a wide range of biological processes at least in part by interacting with proteins and microRNAs. CircRNAs expressed in the hematopoietic compartment have been increasingly recognized as modulators of physiological and pathological features of hematopoetic stem cell (HSC)-derived populations. In particular, several circRNAs were found to enhance or suppress tumor progression in blood malignancies such as leukemias and lymphomas. Moreover, numerous circRNAs have been proposed to help confer resistance to the conventional treatments used in hematopoietic cancers. Here, we review the most important circRNAs described thus far in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), lymphomas, and multiple myeloma (MM). We discuss the usefulness of circRNAs as diagnostic and prognostic markers and their potential value as therapeutic targets.

BACKGROUND: Hematologists deal every day with high mortality rates of acute leukemia patients. Many times these patients need Intensive Care Unit (ICU) support and some general ICU teams believe that these patients have a much greater chance of dying than patients with other pathologies. In Brazil, data related to mortality rates and ICUs for acute leukemia patients are scarce.
METHODS: Therefore, to assess mortality predictors in patients with acute leukemia admitted to a specialized hematological ICU, we evaluated demographics, supportive care, hospitalization time, disease status, admitting diagnosis, neutropenia, number of transfusions and Acute Physiology and Chronic Health Evaluation (APACHE)/Sepsis Related Organ Failure Assessment (SOFA) scores as possible factors associated with mortality. Data were extracted from the first admission records of 110 patients with acute leukemia admitted to the Hemocentro de Pernambuco (Hemope) ICU between 2006 and 2009.
RESULTS: In this retrospective cohort study, 72/110 of the patients were men, and 64/110 were from the metropolitan area of Recife. The patients\' age median was 43.5 years (±17.9); 67.3% had acute myeloid leukemia (AML) and 32.7% had acute lymphoid leukemia. The main admitting diagnosis in the ICU was sepsis (66.7%). The mean APACHE II score was 18.3. Of the total, 65 (59%) died, and the mortality rate was independently related to longer hospitalization (p<0.001), the increase in the APACHE II score (p<0.038) and having received hemodialysis (p<0.006). Neutropenia, receiving multiple transfusions and using any kind of mechanical ventilation or vasoactive drug on admission were not relevant to mortality. Factors associated with higher mortality rates were: longer hospitalization, increase in the APACHE II score, and use of hemodialysis.
CONCLUSIONS: With these data, to prevent organ lesions before admission to the ICU, a better strategy might be to reduce mortality for leukemia patients.

There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram-negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient\'s thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients.