CAR NK cell therapy is expected to be developed to treat acute myeloid leukemia (AML). C-type lectin-like molecule 1 (CLL-1) is a candidate target. However, AML cells with minimal CLL-1 expression (CLL-1dim) may not be eliminated by CAR NK cells. Here we demonstrate that cord blood (CB)-derived NK cells transduced with a novel high-affinity CAR that recognizes CLL-1 can eliminate CLL-1dim AML cells. A newly established anti- CLL-1 monoclonal antibody (mAb) designated as 2-23 exhibits a higher affinity for CLL- 1 than the widely used anti-CLL-1 mAb M26. CB-derived NK cells transduced with a CAR derived from 2-23, but not M26, killed CLL-1dim AML cells in vitro. Additionally, treatment with 2-23 CAR NK cells, but not M26 CAR NK cells, significantly enhanced the survival of the mice transplanted with CLL-1dim AML cells in vivo. Furthermore, in AML patient-derived xenograft models, the 2-23 CAR NK cells expanded robustly, persisted, and eradicated AML cells.

CD163 positive tumour associated macrophages (TAMs) are associated with poor response to immunochemotherapy in patients with diffuse large B cell lymphoma and comprise a significant proportion of the tumour microenvironment. Targeting these TAMs to reverse immunosuppression is an attractive approach for improving treatment response rates. A change in microRNA expression has the potential to modify hundreds of genes by interacting with multiple messenger RNA targets, thereby altering the wider cellular transcriptional profile. The manipulation of microRNAs that control macrophage behaviour may switch the global transcriptomic profiles of immunosuppressive macrophages to more activated, anti-tumour states resulting in the reversal of immune resistance and enhancement of monoclonal antibody (mAb) therapy. Our studies show a significant upregulation of microRNA 142-5p in immunosuppressive macrophages stimulated with IL4/IL13 compared to LPS/IFNγ stimulated macrophages and non-polarised controls. This upregulation of microRNA 142-5p in macrophages stimulated with immunoinhibitory cytokines IL10 and TGFbeta was also demonstrated. Inhibition of microRNA 142-5p expression in IL4/IL13 stimulated macrophages led to a significant increase in FcγRIIIA, CD40 and CD47 expression with enhanced phagocytosis of CLL cells opsonised with Rituximab when compared with non-transfected controls. Expression of microRNA 142-5p in diagnostic DLBCL patient samples was assessed using miRScope assays. These were combined with immunohistochemistry staining of CD206 to identify immunosuppressive macrophages. Combination of high microRNA 142-5p and CD206 expression correlated with a reduction in progression free survival following standard Rituximab containing chemotherapy regimens in 38 patients. Together these studies indicate the potential of targeting microRNA to repolarise macrophages and improve treatment success.

Targeting protein translation is a promising strategy in oncology, especially for malignancies dependent on short-lived survival factors. The clinical translation inhibitor homoharringtonine (HHT) was recently discontinued in the U.S. due to poor solubility and cardiotoxicity, creating an urgent need for new leads. We investigated structurally distinct Amaryllidaceae alkaloids, narciclasine (NCS), lycorine (LYC), and haemanthamine (HAEM), in models of chronic lymphocytic leukemia (CLL) and Richter transformation (RT). Using an optimized 10 L Soxhlet extraction of 'Carlton' daffodil bulbs, an unprecedented NCS yield of 250 mg/kg was achieved, doubling previous laboratory records. NCS showed potent activity against primary CLL cells and the RT-derived HPRT1 line (IC50 = 50 nM), while normal T-cell viability remained largely unaffected at doses producing near-complete CLL cell depletion, indicating a favorable therapeutic window. O-Propargyl-puromycin incorporation and [3H]-leucine assays confirmed dose-dependent inhibition of de novo protein synthesis, triggering selective depletion of the short-lived anti-apoptotic protein Mcl-1 while leaving stable Bcl-2 unaffected. Mcl-1 loss induced mitochondrial depolarization, Annexin V/PI positivity, and PARP cleavage. Combination studies with the Bcl-2 inhibitor venetoclax revealed synergistic activity across all compounds, most pronounced for HAEM, consistent with its comparatively modest Mcl-1 depletion. These findings establish that Amaryllidaceae alkaloids exploit the ″translational addiction″ of leukemia cells to Mcl-1 and validate the isocarbostyril and phenanthridine scaffolds as mechanistically characterized leads. SAR-guided analogue optimization to improve pharmacokinetic properties while preserving the translational inhibition pharmacophore represents the planned next stage of this program.

A 12-year-old female spayed Irish wolfhound presented with a 6-month history of weight loss, chronic vomiting and diarrhoea and a persistent progressive lymphocytosis with previously diagnosed CD8+ T-cell chronic lymphocytic leukaemia (CLL). CLL was initially diagnosed through flow cytometry of EDTA-preserved peripheral blood. The decision to treat was based on a progressive circulating neoplastic lymphocytic population in the face of clinical deterioration. Progressive clinical decline was identified in the several weeks after commencement of treatment with chlorambucil and pegylated asparaginase for progressive CLL. Repeated haemogram and blood smear were suggestive of a second morphologically distinct circulating neoplastic population. Repeated flow cytometry of peripheral blood was consistent with a concurrent acute myeloid leukaemia (AML) to previously identified CD8+ CLL. Emergence of AML coincided with development of upwards of five cutaneous lesions, with concern for leukaemia cutis. High-dose chemotherapy with vincristine (0.7 mg/m[2]) was commenced. Despite more aggressive treatment, rapid clinical deterioration ensued, and euthanasia was elected. To the author's knowledge, this is the first report of diagnosis of concurrent AML and CLL in a dog.

Chronic Lymphocytic Leukemia (CLL) and Chronic Myeloid Leukemia (CML) are two distinct hematological malignancies with different pathophysiologies and clinical courses. While each is relatively common in the elderly population, their simultaneous occurrence in a single patient is exceptionally rare and poses diagnostic and therapeutic challenges. We present the case of a 79-year-old male who was evaluated for progressive fatigue, weight loss, and marked leukocytosis. Laboratory investigations, peripheral blood smear, flow cytometry, and molecular studies were utilized to establish the diagnosis. Initial findings revealed extreme leukocytosis, anemia, and elevated LDH. Peripheral smear and molecular testing confirmed CML through detection of the BCR::ABL1 fusion gene. Concurrently, flow cytometry identified a clonal B-cell population positive for CD5, CD19, and CD20, consistent with CLL. Imaging showed splenomegaly and pathologic lymphadenopathy. The patient was treated with imatinib and hydroxyurea, resulting in normalization of white blood cell count, though anemia and thrombocytopenia persisted. This case highlights a rare synchronous diagnosis of CML and CLL in an elderly patient. The comprehensive diagnostic evaluation was critical in establishing the dual pathology. The case underscores the need for heightened clinical suspicion in atypical presentations and contributes to the limited body of knowledge on coexistent myeloid and lymphoid malignancies.

Bruton's tyrosine kinase (BTK) plays an important role in B-cell development and has become a well-established target in B-cell malignancies. Over the past two decades, BTK inhibitors (BTKis) have transformed the treatment landscape for chronic lymphocytic leukemia (CLL) and other B-cell lymphoid malignancies. Despite their efficacy, acquired resistance to BTKis remains a significant challenge, highlighting the need for alternative therapeutic strategies. Targeted protein degradation has emerged as a promising approach to eliminate BTK and thereby inhibit both its kinase and non-kinase (i.e. scaffold) functions. Bexobrutideg (NX-5948) is a novel BTK degrader that was designed to overcome limitations associated with BTKis while maintaining favorable selectivity. In this review, we summarize the rationale for BTK degradation, discuss the preclinical and clinical evidence supporting bexobrutideg, and highlight remaining challenges and future directions for this emerging class of therapeutics.

Although Immune cytopenias such as immune thrombocytopenia (ITP), autoimmune haemolytic anaemia (AIHA) and pure red blood cell aplasia (PRCA) are well documented associations with chronic lymphocytic leukaemia (CLL), aplastic anaemia (AA) is seemingly rare.

Chronic lymphocytic leukemia (CLL) is highly heterogeneous both clinically and biologically. Although genetic factors have been identified, several lines of evidence suggest a role for environmental factors in disease onset and progression. Diet is a recognized risk factor for various diseases, including cancer, with an established relationship to the composition of the gut microbiome. Taking advantage of the widely used Eμ-TCL1 transgenic model, we investigated the relationship between diet, the gut microbiota, and CLL development. We randomized a cohort of Eμ-TCL1 mice to receive a normal standard diet (N) (n = 15) or an experimental diet rich in low-complexity carbohydrates and lower in proteins and fibers (HC/LPF) (n = 16) and observed a progressive shift in microbiome composition in animals fed with the HC/LPF diet, accompanied by an acceleration of disease progression and shortened survival. These effects were associated with an increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes in mice fed with the HC/LPF diet. Our data suggest a close link between the HC/LPF diet and Oscillospira, Ruminococcus, Mucispirillum, AF12, and Rikenella genera, possibly affecting CLL development. The present work paves the way for detailed studies to be conducted in controlled cohorts of patients with CLL to elucidate the role of diet in disease incidence and evolution.

Phosphoinositide 3-kinases (PI3Ks) are major regulators of cell growth, proliferation and signalling, constituting key therapeutic targets in cancer, inflammation, and other diseases. Individual class I PI3K isoforms control key cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3Kδ inhibitor that shows promise for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we describe the mechanism driving roginolisib's potent and isoform-selective inhibition of PI3Kδ. Roginolisib uniquely stabilises the catalytic C-terminal helix kα12, locking the enzyme in an inactive conformation. This binding mode also results in more sustained inhibition of phosphatidylinositol 3,4,5-trisphosphate formation in tumour samples of CLL patients. Inhibition of PI3Ks by stabilization of helix kα12 into an inactive conformation has not, to the best of our knowledge, been described before and may provide the basis for novel, more selective and effective pharmacological strategies.

Transitioning from its traditional conceptualization as a static scaffold, the extracellular matrix (ECM) is now recognized as a dynamic regulatory hub that integrates biomechanical cues with biochemical signaling to dictate cellular fate and physiological stability. Central to this regulatory network is Fibromodulin (FMOD), a Class II small leucine-rich proteoglycan (SLRP) that integrates structural scaffolding with complex signaling modulation. This review synthesizes the molecular topography of FMOD, detailing how its signature horseshoe-shaped solenoid fold facilitates high-affinity docking with type I and II collagens to orchestrate fibrillogenesis. We delineate FMOD's dual functionality as a structural architect, responsible for matrix tensile integrity, and as a biochemical supervisor that sequesters and titrates growth factor bioavailability, specifically within the transforming growth factor-beta (TGF-β) superfamily. Under physiological conditions, FMOD-mediated matrix organization is essential for musculoskeletal resilience and ocular transparency; however, its dysregulation functions as a context-dependent amplifier and modifier of tissue pathology. We analyze the mechanistic shift where FMOD promotes aberrant collagen cross-linking in fibrotic visceral organs, contrastingly drives scleral thinning in myopia, and facilitates the assembly of a desmoplastic "stromal shield" within the tumor microenvironment. Furthermore, the ectopic overexpression of FMOD in B-cell chronic lymphocytic leukemia (B-CLL) highlights its clinical utility as a highly specific diagnostic biomarker and a viable target for TCR-based immunotherapies. By linking biomechanical cues to intracellular cascades, FMOD serves as a critical rheostat of the matrisome, offering a unique molecular target to disrupt pathological stroma and restore tissue homeostasis.