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Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant disease in which hematopoietic cell apoptosis may play an important pathophysiological role. Previous studies of the content of phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) indicated the possibility of remote transmission of anti-apoptotic signals between pathological and normal hematopoietic progenitors.The study determined the plasma levels of beta chemokines and cytokines in N = 19 patients with PNH and 31 healthy controls. The research material was peripheral blood plasma (EDTA) stored at -80 °C until the test. Beta chemokine and cytokine concentrations were tested in duplicate with Bio-Plex Pro Human Cytokine Assay (Bio-Rad, Hercules, CA, USA) using a Luminex 200 flow cytometer and xPONENT software (Luminex Corporation, Austin, TX, USA). In peripheral blood CD34+ cells we tested the proportions of PI(3,4,5)P3+ and Annexin binding apoptotic phenotype using FC and phosflow.Compared to the control group, the PNH group showed a significant increase in the plasma concentration of some beta chemokines and cytokines, including MIP-1alpha/CCL3, eotaxin/CCL11, MCP1/CCL2, IL4 and G-CSF. In the group of PNH patients, a significant decrease in the concentration of some cytokines was also observed: RANTES/CCL5, MIP-1beta/CCL4, PDGF-BB and IL9. At the same time, the plasma concentrations of the chemokine IP-10/CXCL10 and the cytokines IFN-gamma, TNF, IL6 and IL10 showed no significant deviations from the values for the control group. Anti-apoptotic phenotype and phosphatidylinositol (3,4,5)-trisphosphate content in PNH clone of CD34+ cells were associated with the level of CCL3 and negatively associated with CCL5, CCL4, PDGF-BB and IL9.This data suggest the existence of apoptotic and PI(3,4,5)P3 imbalance in PNH CD34+ cells driven by anti-apoptotic cytokine biosignature in PNH. Plasma cytokines and intracellular enzymes that regulate the phosphoinositide pathways may become a therapeutic target in PNH.

Transcriptional deregulation of multiple oncogenes, tumor suppressors and survival pathways is a cancer cell hallmark. Super enhancers (SE) are long stretches of active enhancers in close linear proximity that ensure extraordinarily high expression levels of key genes associated with cell lineage, function and survival. SE landscape is intrinsically prone to changes and reorganization during the course of normal cell differentiation. This functional plasticity is typically utilized by cancer cells, which remodel their SE landscapes to ensure oncogenic transcriptional reprogramming. Multiple recent studies highlighted structural genetic mechanisms in non-coding regions that create new SE or hijack already existing ones. In addition, alterations in abundance/activity of certain SE-associated proteins or certain viral infections can elicit new super enhancers and trigger SE-driven transcriptional changes. For these reasons, SE profiling emerged as a powerful tool for discovering the core transcriptional regulatory circuits in tumor cells. This, in turn, provides new insights into cancer cell biology, and identifies main nodes of key cellular pathways to be potentially targeted. Since SEs are susceptible to inhibition, their disruption results in exponentially amassing 'butterfly' effect on gene expression and cell function. Moreover, many of SE elements are druggable, opening new therapeutic opportunities. Indeed, SE targeting drugs have been studied preclinically in various hematologic malignancies with promising effects. Herein, we review the unique features of SEs, present different cis- and trans-acting mechanisms through which hematologic tumor cells acquire SEs, and finally, discuss the potential of SE targeting in the therapy of hematologic malignancies.

Elevated tumor necrosis factor (TNF) and its soluble receptors (p55 and p75) plasma levels in patients with non-Hodgkin's lymphoma (NHL) have been shown to correlate with various adverse prognostic factors and predict poor NHL outcome. In vitro studies demonstrated that TNF expression level could be influenced by TNF-376, -308, -238, -163 promoters' polymorphisms. To explore whether these polymorphisms confer the susceptibility to and influence NHL outcome, we genotyped the TNF-376, -308, -238, -163 polymorphisms in 204 NHL patients and 96 healthy controls. The frequency and distribution of polymorphic alleles were similar in both studied groups. TNF-308A was the only polymorphic allele related to elevated TNF, p55, p75 plasma levels (p = 0.009, p = 0.03, p = 0.007, respectively), lower complete remission rate (p = 0.01), higher progression (p = 0.06) and death (p = 0.01) incidences. TNF-308A was the sole allele of independent prognostic significance for shorter freedom from progression (FFP) and overall survival (OS) (p = 0.009 and p = 0.017, respectively). These data indicate that innate immunity as reflected by the genetic propensity of the host to regulate TNF expression influences clinical course and outcome of NHL.

The role of tumor necrosis factor (TNF)-308A polymorphic allele on non-Hodgkin's lymphoma (NHL) outcome was documented in the previous studies, although the role of the neighboring polymorphisms was unknown. The aim of the present study was to asses the frequencies and distributions of the HLA DRB1, TNF-308 and lymphotoxin alpha (LTalpha)+252 allelic polymorphisms in NHL patients and healthy controls and their influence on NHL outcome. The HLA DRB1, TNF-308 and LTalpha +252 allelic frequencies and distributions didn't differ significantly between patients and healthy controls, thus it is unlikely that polymorphisms within the above mentioned sites confer susceptibility for lymphoma occurrence. Among the polymorphic alleles HLA DRB1*03, TNF-308A and LTalpha +252A remaining in linkage disequilibrium, TNF-308A was the only allele associated with higher TNF and its p55 and p75 receptors' plasma levels (p = 0.009, p = 0.03, and p = 0.007), lower complete remission rates (p = .006), shorter freedom from progression (FFP) and overall survival (OS) (p = 0.009 and p = 0.017, respectively). Among the polymorphic HLA DRB1 alleles, null HLA DRB1*02 was the sole allele along with the TNF-308A that remained independent factors for shorter FFP (relative risk [RR] = 1.18, p0.02 and RR = 1.63, p0.0001, respectively) and OS (RR = 1.25, p0.0001 and RR = 1.51, p0.0001, respectively). Innate immunity reflected by inherited HLA DRB1 genes repertoire and genetic propensity of the host to regulate TNF production and/or other closely linked genes influences clinical course and outcome of NHL.

In order to define more accurately the role of multidrug resistance (MDR)-related protein (mrp) gene in chronic lymphocytic leukemia (CLL), we addressed the question of its expression pattern in isolated peripheral blood B lymphocytes in seven healthy donors and 28 patients with CLL, with respect to some laboratory and clinical parameters of the disease. For this purpose, we used a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), based on the coamplification of an internal standard not homologous to the DNA target to quantify the mrp transcription level in each studied sample. We report that the level of constitutive mrp gene's expression in peripheral blood lymphocytes is higher in CLL patients than in healthy controls. We found increased mrp gene expression levels in patients with higher white blood cells (WBC) and lymphocytes' counts as well as in more advanced disease stages according to Rai or Binet scale. Finally, mrp gene's expression was higher in patients with progressive CLL, especially in cases refractory to chemotherapy salvage. The results of the present study suggest that expression of mrp gene might be relevant in the pathogenesis of the MDR phenotype in CLL.