Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity.

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines.

Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy.

Unlabelled: Alterations in epigenetic marks, such as DNA methylation, represent a hallmark of cancer that has been successfully exploited for therapy in myeloid malignancies. Hypomethylating agents (HMA), such as azacitidine, have become standard-of-care therapy to treat myelodysplastic syndromes (MDS), myeloid neoplasms that can evolve into acute myeloid leukemia. However, our capacity to identify who will respond to HMAs, and the duration of response, remains limited.

Epigenetic targets in B- and T-cell lymphomas: latest developments.

Non-Hodgkin's lymphomas (NHLs) comprise a diverse group of diseases, either of mature B-cell or of T-cell derivation, characterized by heterogeneous molecular features and clinical manifestations. While most of the patients are responsive to standard chemotherapy, immunotherapy, radiation and/or stem cell transplantation, relapsed and/or refractory cases still have a dismal outcome. Deep sequencing analysis have pointed out that epigenetic dysregulations, including mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases (DNMTs), are prevalent in both B- cell and T-cell lymphomas.

G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy.

Background: Immunotherapy-based regimens have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decades; however, most disease subtypes remain almost incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory (R/R) B-NHL patients either as a single-agent or in combination with ublituximab, a new generation CD20 antibody.

Methods: A set of eight B-NHL cell lines and primary samples were cultured in the presence of bone marrow-derived stromal cells, M2-polarized primary macrophages, and primary circulating PBMCs as a source of effector cells.

RHOA Therapeutic Targeting in Hematological Cancers.

Primarily identified as an important regulator of cytoskeletal dynamics, the small GTPase Ras homolog gene family member A (RHOA) has been implicated in the transduction of signals regulating a broad range of cellular functions such as cell survival, migration, adhesion and proliferation. Deregulated activity of RHOA has been linked to the growth, progression and metastasis of various cancer types. Recent cancer genome-wide sequencing studies have unveiled both gain and loss-of-function mutations in primary leukemia/lymphoma, suggesting that this GTPase may exert tumor-promoting or tumor-suppressive functions depending on the cellular context.

Exportin 1-mediated nuclear/cytoplasmic trafficking controls drug sensitivity of classical Hodgkin's lymphoma.

Exportin 1 (XPO1) is the main nuclear export receptor that controls the subcellular trafficking and the functions of major regulatory proteins. XPO1 is overexpressed in various cancers and small inhibitors of nuclear export (SINEs) have been developed to inhibit XPO1. In primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL), the XPO1 gene may be mutated on one nucleotide and encodes the mutant XPO1 .

Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma.

Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death.

Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing.

Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1).

Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma.

Protein ubiquitylation coordinates crucial cellular events in physiological and pathological conditions. A comparative analysis of the ubiquitin proteome from bortezomib (BTZ)-sensitive and BTZ-resistant mantle cell lymphoma (MCL) revealed an enrichment of the autophagy-lysosome system (ALS) in BTZ-resistant cells. Pharmacological inhibition of autophagy at the level of lysosome-fusion revealed a constitutive activation of proteaphagy and accumulation of proteasome subunits within autophagosomes in different MCL cell lines with acquired or natural resistance to BTZ.

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas.

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte's life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium.

Recent advances in the pharmacological targeting of ubiquitin-regulating enzymes in cancer.

As a post-translational modification that has pivotal roles in protein degradation, ubiquitination ensures that intracellular proteins act in a precise spatial and temporal manner to regulate diversified cellular processes. Perturbation of the ubiquitin system contributes directly to the onset and progression of a wide variety of diseases, including various subtypes of cancer. This highly regulated system has been for years an active research area for drug discovery that is exemplified by several approved drugs.

Histone Modifications and Their Targeting in Lymphoid Malignancies.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes.

Prognostic impact of micromegakaryocytes in primary myelodysplastic syndromes.

Micromegakaryocytes (microMKs) are considered a myelodysplastic feature of myeloid neoplasms in adults, with an adverse prognosis connotation. However, this notion in MDS has not been well proved. In our cohort of 287 MDS, patients with microMKs showed lower overall survival (OS) (HR, 2.

Antitumor Activity of the Novel BTK Inhibitor TG-1701 Is Associated with Disruption of Ikaros Signaling in Patients with B-cell Non-Hodgkin Lymphoma.

Purpose: Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored.

Experimental Design: A set of six clinical samples from an ongoing phase I trial dosing patients with chronic lymphocytic leukemia (CLL) with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA sequencing (RNA-seq) analysis.

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage.

Immune-Checkpoint Inhibitors in B-Cell Lymphoma.

For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors.

[50 years of the Neonatal Screening Program in Catalonia.].

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation.

Management of Drug Resistance in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis.