Search results for "Lymphocytic"
showing 10 items of 167 documents
Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence
2018
Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in…
Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1
2021
Abstract Richter’s transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase–associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurren…
Chronic Myelogenous Leukemia: Approaches to Pharmacological Resistance
2017
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the reciprocal t (9:22) chromosomal translocation. This rearrangement produces the socalled Philadelphia chromosome carrying the chimeric Bcr-Abl oncoprotein, p210, responsible of disease progression [1]. Because of its critical role in pathogenesis, the scientific community had focused on targeting Bcr–Abl for treatment of CML. For many years Imatinib (IM), as selective inhibitor of the Tyr-Kinase activity of the oncoprotein, was used to treat CML patients [2]. From 2000 some data relative to IM resistance were available. There are many mechanisms responsible of IM resistance, more often point mutat…
The B-cell receptor in control of tumor B-cell fitness: Biology and clinical relevance
2019
Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B-cell lymphoproliferative disorders retain surface BCR expression, including B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B-NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B-NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC-driven mouse B-cell lymphoma model have revisited the role of …
Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins
2017
Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensiti…
AB0458 A PHASE II RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF OF CONCEPT STUDY OF ORAL SELETALISIB IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROM…
2019
Background: Seletalisib is a potent, selective oral inhibitor of phosphoinositide-3 kinase delta (PI3Kδ). Preclinical data have shown that the PI3Kδ pathway is upregulated within salivary glands of patients with PSS and contributes to disease pathogenesis.1 Objectives: To assess the efficacy and safety of seletalisib in patients with PSS. Methods: In this Phase II, double-blind, proof of concept study (NCT02610543), patients with PSS having an EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) score ≥5 were randomised 1:1 to seletalisib once daily or placebo (PBO) in addition to current PSS therapy for 12 weeks. The primary endpoint was change from baseline in ESSDAI at Week 12. The s…
Early ROS-mediated DNA damage and oxidative stress biomarkers in Monoclonal B Lymphocytosis
2012
Monoclonal B Lymphocytosis (MBL) is defined as asymptomatic monoclonal B-cell expansion characterised by a CLL-phenotype, but with less than 5 x 10(9)/I circulating cells. Reactive oxygen species (ROS)-mediated cell damage plays a critical role in the initiation of carcinogenesis as well as in malignant transformation. The goal of this study was to perform an analysis of the oxidative stress statuses of patients affected by MBL and chronic lymphocytic leukaemia (CLL). We examined peripheral blood and urine specimens from 29 patients with MBL, 55 with CLL and 31 healthy subjects. There was a significant increase in the occurrence of the mutagenic base 8-oxo-2'-deoxiguanosine (8-oxo-dG) in th…
CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death
2011
Abstract Extracellular adenosine (ADO), generated from ATP or ADP through the concerted action of the ectoenzymes CD39 and CD73, elicits autocrine and paracrine effects mediated by type 1 purinergic receptors. We have tested whether the expression of CD39 and CD73 by chronic lymphocytic leukemia (CLL) cells activates an adenosinergic axis affecting growth and survival. By immunohistochemistry, CD39 is widely expressed in CLL lymph nodes, whereas CD73 is restricted to proliferation centers. CD73 expression is highest on Ki-67+ CLL cells, adjacent to T lymphocytes, and is further localized to perivascular areas. CD39+/CD73+ CLL cells generate ADO from ADP in a time- and concentration-dependen…
Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study.
2011
To retrospectively assess the efficacy of bendamustine alone and with rituximab (R-B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39-85). Forty-three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1-8). Twenty-two patients received bendamustine alone and 87 patients received R-B (median B dosage: 100 mg/m(2) per day, range 90-130 mg/m(2) per day). The overall response rate was 69·6% (complete response 28·6%; partial response 41%), and was significantly higher in patients treated with R-B (P = 0·014) and in those responsive to the previous treatment (P=0·…
A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematolog…
2006
Abstract Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle. Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasm…