Search

Simple Summary: In chronic lymphocytic leukemia (CLL), abnormal B lymphocytes accumulate in the bone marrow (BM) and secondary lymphoid tissues. The BM and lymph nodes support angiogenesis and increased vascularization. Although certain drugs approved by the US Food and Drug Administration improve clinical outcomes, some patients do not respond and others relapse. Interactions between CLL cells and the tissue microenvironment favor leukemic cell trafficking, survival, and proliferation via the production of soluble factors. Some of these factors exhibit pro-angiogenic properties. This review summarizes the biology of these molecules with survival/pro-angiogenic value, and provides a summary of new, selective inhibitors targeting these molecules (and their receptors) currently under evaluation in preclinical and clinical studies. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes in the blood. These cells migrate to and proliferate in the bone marrow and lymphoid tissues. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur; novel treatment approaches are therefore still needed. Inhibition of the angiogenesis involved in the progression of CLL might be a relevant therapeutic strategy. The literature data indicate that vascular endothelial growth factor, angiopoietin-2, and matrix metalloproteinase-9 are pro-angiogenic factors in CLL. A number of other CLL factors might have pro-angiogenic activity: fibroblast growth factor-2, certain chemokines (such as CXCL-12 and CXCL-2), tumor necrosis factor-α, insulin-like growth factor-1, neutrophil gelatinase-associated lipocalin, and progranulin. All these molecules contribute to the survival, proliferation, and migration of CLL cells. Here, we review the literature on these factors' respective expression profiles and roles in CLL. We also summarize the main results of preclinical and clinical trials of novel agents targeting most of these molecules in a CLL setting. Through the eradication of leukemic cells and the inhibition of angiogenesis, these therapeutic approaches might alter the course of CLL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B lymphocytes that escape death, and correlates with the expression of negative prognostic markers such as the CD38 antigen. Although certain new drugs approved by the US Food and Drug Administration improve the clinical outcome of CLL patients, drug resistance and disease relapse still occur. Like CD38, neutrophil gelatinase-associated lipocalin receptor (NGAL-R) is frequently overexpressed in CLL cells. Here, we evaluated the concomitant surface expression of NGAL-R and CD38 in leukemic blood cells from 52 CLL patients (37 untreated, 8 in clinical remission, and 7 relapsed). We provide evidence of a positive correlation between NGAL-R and CD38 levels both in the interpatient cohorts (p < 0.0001) and in individual patients, indicating a constitutive association of NGAL-R and CD38 at the cell level. Patients with progressing CLL showed a time-dependent increase in NGAL-R/CD38 levels. In treated CLL patients who achieved clinical remission, NGAL-R/CD38 levels were decreased, and were significantly lower than in the untreated and relapsed groups (p < 0.02). As NGAL-R and CD38 participate in CLL cell survival, envisioning their simultaneous inhibition with bispecific NGAL-R/CD38 antibodies capable of inducing leukemic cell death might provide therapeutic benefit for CLL patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B lymphocytes in the peripheral components of the immune system. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur. In the bone marrow and secondary lymphoid tissues, the trafficking, survival, and proliferation of leukemic B cells are regulated by interactions with the microenvironment (via cell-extracellular matrix interactions, cell-cell contacts, and the exchange of soluble factors) and contribute to treatment resistance. Here, we review the biology of the extracellular vesicles released into this microenvironment with cross-talk between neoplastic B cells and neighboring or remote target cells. A better understanding of the extracellular vesicles' role in CLL progression and drug resistance might open up opportunities for the development of novel therapeutics that target the pro-survival dialogue between tumor cells and the tumor microenvironment. In addition to intrinsic genomic and nongenomic alterations, tumor progression is also dependent on the tumor microenvironment (TME, mainly composed of the extracellular matrix (ECM), secreted factors, and bystander immune and stromal cells). In chronic lymphocytic leukemia (CLL), B cells have a defect in cell death; contact with the TME in secondary lymphoid organs dramatically increases the B cells' survival via the activation of various molecular pathways, including the B cell receptor and CD40 signaling. Conversely, CLL cells increase the permissiveness of the TME by inducing changes in the ECM, secreted factors, and bystander cells. Recently, the extracellular vesicles (EVs) released into the TME have emerged as key arbiters of cross-talk with tumor cells. The EVs' cargo can contain various bioactive substances (including metabolites, proteins, RNA, and DNA); upon delivery to target cells, these substances can induce intracellular signaling and drive tumor progression. Here, we review recent research on the biology of EVs in CLL. EVs have diagnostic/prognostic significance and clearly influence the clinical outcome of CLL; hence, from the perspective of blocking CLL-TME interactions, EVs are therapeutic targets. The identification of novel EV inhibitors might pave the way to the development of novel combination treatments for CLL and the optimization of currently available treatments (including immunotherapy). [ABSTRACT FROM AUTHOR]

Simple Summary: Since the identification of a large variety of biomarkers in B cell malignancies as being driving factors for tumor progression and patient prognosis, their targeting may confer valuable options for the treatment of these diseases. Over the past 20 years, the permanent development of a multitude of inhibitors acting on survival-associated biomarkers has made it into clinical evaluation in B lymphoid tumors. Although certain drugs approved by the US Food and Drug Administration improve clinical outcome, some patients do not respond and others relapse. This review summarizes the current state-of-the-art, provides a summary of new, safer, more selective inhibitors currently under evaluation in clinical trials, and highlights the emerging positioning of metabolic drugs in tumor B cell biology as a promising strategy to be translated into clinical practice. Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today's commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton's tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody–drug conjugates, antibody–radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders. [ABSTRACT FROM AUTHOR]

Besides their antiviral and immunomodulatory functions, type I (α/β) and II (γ) interferons (IFNs) exhibit either beneficial or detrimental effects on tumor progression. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal CD5+ B lymphocytes that escape death. Drug resistance and disease relapse still occur in CLL. The triggering of IFN receptors is believed to be involved in the survival of CLL cells, but the underlying molecular mechanisms are not yet characterized. We show here that both type I and II IFNs promote the survival of primary CLL cells by counteracting the mitochondrial (intrinsic) apoptosis pathway. The survival process was associated with the upregulation of signal transducer and activator of transcription-3 (STAT3) and its target anti-apoptotic Mcl-1. Furthermore, the blockade of the STAT3/Mcl-1 pathway by pharmacological inhibitors against STAT3, TYK2 (for type I IFN) or JAK2 (for type II IFN) markedly reduced IFN-mediated CLL cell survival. Similarly, the selective Src family kinase inhibitor PP2 notably blocked IFN-mediated CLL cell survival by downregulating the protein levels of STAT3 and Mcl-1. Our work reveals a novel mechanism of resistance to apoptosis promoted by IFNs in CLL cells, whereby JAKs (TYK2, JAK2) and Src kinases activate in concert a STAT3/Mcl-1 signaling pathway. In view of current clinical developments of potent STAT3 and Mcl-1 inhibitors, a combination of conventional treatments with these inhibitors might thus constitute a new therapeutic strategy in CLL. [ABSTRACT FROM AUTHOR]

The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment. [ABSTRACT FROM AUTHOR]

Human neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein present in a wide variety of tissues and cell types. NGAL exists as a 25 kDa monomer, a 46 kDa homodimer (the most abundant form in healthy subjects) and a 130 kDa disulfide-linked heterodimer bound to latent matrix metalloproteinase-9. Dysregulated expression of NGAL in human malignancies suggests its value as a clinical marker. A growing body of evidence is highlighting NGAL's paradoxical (i.e., both beneficial and detrimental) effects on cellular processes associated with tumor development (proliferation, survival, migration, invasion, and multidrug resistance). At least two distinct cell surface receptors are identified for NGAL. This review (i) summarizes our current knowledge of NGAL's expression profiles in solid tumors and leukemias, and (ii) critically evaluates the beneficial and detrimental activities of NGAL having been documented in a diverse range of cancer-derived cell lines. A better understanding of the causal relationships between NGAL dysregulation and tumor development will require a fine analysis of the molecular aspects and biological role(s) of NGAL both in primary tumors and at different stages of disease. Having an accurate picture of NGAL's contribution to tumor progression is a prerequisite for attempting to modulate this protein as a putative therapeutic target. [ABSTRACT FROM AUTHOR]

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans , apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.