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Chronic lymphocytic leukemia (CLL) is a heterogeneous B cell malignancy characterized by the accumulation of functionally incompetent B lymphocytes. Despite the availability of highly effective treatments, CLL remains incurable, and the factors contributing to disease progression are not fully understood. Autoimmune complications frequently arise in CLL patients and are associated with poor clinical prognosis. This study investigates the connection between plasma cell-mediated autoimmunity and CLL progression using a mouse model that expresses an active Receptor Activator of NF-κB (RANK) in B cells (RK mice), where autoimmune manifestations coexist with CLL. Transcriptional profiling of RANK-driven leukemic cells revealed a more indolent form of CLL compared to the classical TCL1 model. The discovery of near-identical CDR3 regions in both plasma and CLL cells of RK mice suggests a shared progenitor and antigen driving both conditions. Deletion of Blimp-1, which prevents plasma cell differentiation, initially enhanced B1/CLL formation in young mice but nearly halted CLL progression, highlighting the significant influence of autoimmune complications on disease outcomes. This research underscores the intertwined nature of autoimmunity and CLL, suggesting that targeting inflammatory pathways could offer therapeutic potential for managing both conditions. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) signaling pathway is a central regulator of B cell biology, influencing survival, proliferation, metabolism, and immune responses. This Review explores how in both normal and malignant B cells, signaling operates within a finely tuned “comfort zone”, where appropriate levels support cell growth and survival. This comfort zone is dynamically modulated by the developmental stage, costimulatory signals, and the duration, magnitude, and subcellular localization of signaling events. In chronic lymphocytic leukemia, aberrant PI3K/AKT activation drives disease progression and resistance to therapy. Notably, deviations from the comfort zone—whether through excessive hyperactivation or insufficient signaling—can trigger cell death, presenting therapeutic opportunities. Signaling thresholds influence normal B cell development and chronic lymphocytic leukemia pathogenesis, including mechanisms of immune escape and Richter's transformation, an aggressive progression from chronic lymphocytic leukemia. Therapeutic strategies targeting PI3K/AKT are evaluated, with a focus on challenges such as toxicity. By understanding the nuanced modulation of the signaling comfort zone, we can refine therapies to selectively eliminate leukemic cells while preserving normal B cell function, offering new hope for improved treatment outcomes. [ABSTRACT FROM AUTHOR]

No more help for the cancer: Just as the tumor microenvironment influences the behavior of solid tumors, hematological malignancies are affected by the microenvironment in the bone marrow stroma. Park et al. identified a pathway dependent on protein kinase C-β from the stromal cells, which promotes survival and drug resistance in B cell malignancies. The authors examined the mechanism for the observed effects and then identified small-molecule compounds for potential intervention. Inhibiting the protein kinase C-β signaling pathway in stromal cells sensitized these cancers to a variety of drugs and extended survival in both genetic and patient-derived mouse models of cancer. Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell–autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)–β–dependent signals from bone marrow–derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal–regulated kinase (ERK)–mediated stabilization of B cell lymphoma–extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β–dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies. [ABSTRACT FROM AUTHOR]

The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. [ABSTRACT FROM AUTHOR]

The survival and proliferation of CLL cells depends on microenvironmental contacts in lymphoid organs. CD38 is a cell surface receptor that plays an important role in survival and proliferation signaling in CLL. In this study we demonstrate SYK's direct involvement in the CD38 signaling pathway in primary CLL samples. CD38 stimulation of CLL cells revealed SYK activation. SYK downstream target AKT was subsequently induced and MCL-1 expression was increased. Concomitant inhibition of SYK by the SYK inhibitor R406 resulted in reduced activation of AKT and prevented upregulation of MCL-1. Moreover, short-term CD38 stimulation enhanced BCR-signaling, as indicated by increased ERK phosphorylation. CXCL12-dependent migration was increased after CD38 stimulation. Treating CLL cells with R406 inhibited CD38-mediated migration. In addition, we observed marked downregulation of CD38 expression for CLL cells treated with R406 compared to vehicle control. Finally, we observed a clear correlation between CD38 expression on CLL cells and SYK-inhibitor efficacy. In conclusion, our study provides deeper mechanistic insight into the effect of SYK inhibition in CLL. [ABSTRACT FROM AUTHOR]

B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism. [ABSTRACT FROM AUTHOR]

Summary Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2 , Dusp6 , and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance. [ABSTRACT FROM AUTHOR]