Leukemia Lymphoma Research Articles

Clinical trial participation, clinical care, and patient outcomes by practice setting: a real-world database analysis of patients with Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma.

This study was designed to compare treatment patterns, clinical trial participation, and clinical outcomes among patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) or Mantle cell lymphoma (MCL) by site of care. A nationwide electronic health record (EHR)-derived de-identified database was utilized for this study. Eligible patients were diagnosed with either CLL or MCL from 2013-2022 who received systemic therapy for their disease. Overall survival (OS) was analyzed using Kaplan Meier method, censoring patients without events at last observation in the database. Cox proportional hazards regression model was used to adjust for baseline covariates. A total of 6,372 patients with CLL and 3,411 with MCL met eligibility criteria for this analysis; 13.9% and 22.2%, respectively, were treated in academic settings. Academic settings were associated with higher patient volume and were more likely to treat MCL with CAR-T, enroll patients with CLL or MCL to clinical trials, and care for patients who were younger, White, and for CLL with higher rates of del(17p) mutations (all p < 0.01). Survival was significantly longer among patients treated in academic vs community settings (median OS not reached vs 80.5 months for CLL; 95.6 vs 68.7 months for MCL from start of first-line therapy). Patients who received care in academic settings differed from those treated in the community; care in academic settings was associated with significantly longer OS and higher trial participation. Further research is warranted to better understand the factors that may contribute to the observed outcomes.

Bioinformatic characterization of STING expression in hematological malignancies reveals association with prognosis and anti-tumor immunity

IntroductionStimulator of interferon response cGAMP interactor (STING) is essential for both innate and adaptive immunity. However, a comprehensive molecular characterization of STING expression across hematological malignancies is lacking.MethodsIn this study, the pan-blood-cancer landscape related to STING expression was identified using the GTEx, CCLE, Hemap, and TCGA databases, and the potential value for predicting prognosis was investigated. The relationship between STING expression and immune cell enrichment was assessed in the Hemap database. Moreover, the value of STING in predicting the efficacy of immunotherapy was validated using tumor immune dysfunction and exclusion (TIDE) biomarkers and real-world immunotherapy datasets.Results and DiscussionSTING was found to be relatively highly expressed in acute myeloid leukemia (AML) and chronic myeloid leukemia, with higher STING expression correlated with poorer prognosis in AML. STING expression was positively correlated with immune-related pathways such as IFN-gamma response, IFN-alpha response, and inflammatory response. Cytolytic score and STING expression were positively correlated in some hematological tumors, especially chronic lymphocytic leukemia and mantle cell lymphoma. Interestingly, STING expression was negatively correlated with TIDE biomarkers in AML, suggesting that AML patients with a high STING expression level may benefit from immunologic treatment. Our findings contribute a molecular characterization of STING across hematological malignancies, facilitating the development of individualized prognosis and treatment strategies.

Secondary neoplasms in survivors of pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma: a single-center, retrospective study

BackgroundAcute lymphoblastic leukemia (ALL)-based therapeutic regimens have markedly improved the survival of children with ALL and lymphoblastic lymphoma (LBL). However, survivors are at risk of secondary neoplasms. Few studies on such secondary neoplasms have been conducted outside of Europe and the United States. The aim of this study was to evaluate the incidence of, risk factors for, and outcomes of secondary neoplasms in long-term survivors of ALL and LBL at a tertiary pediatric oncology center in Mie prefecture, Japan.ProcedureWe retrospectively reviewed 188 patients with ALL and LBL who were treated with an ALL-based therapeutic regimen at Mie University Hospital from January 1, 1977 to December 31, 2022 and followed up.ResultsTen patients developed secondary neoplasms, with 10-year and 20-year cumulative incidences of 2.9% [standard error (SE) = 1.5%] and 5.5% (SE = 2.3%), respectively. The median interval between the primary-cancer diagnosis and secondary-neoplasm diagnosis was 18.5 years (range: 7.8–41.7 years). All 10 secondary neoplasms were central nervous system (CNS) tumors (6 meningiomas and 4 high-grade gliomas). Radiotherapy (p = 0.007) and CNS involvement in the primary cancer (p &amp;lt; 0.001) increased the risk of secondary neoplasms among long-term survivors. Gliomas occurred significantly earlier than meningiomas (p = 0.047), and three patients died of secondary neoplasms (all gliomas).ConclusionsAs secondary gliomas occurred earlier than meningiomas and are associated with poor outcomes, physicians should take great pains to minimize their risk to improve long-term survival and quality of life.

Abstract IA07: Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation

Abstract Chimeric Antigen Receptor (CAR) T cell therapy represents a significant advance in the treatment of hematologic malignancies, as demonstrated by the high response rates and improved survival in diseases such as acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Diffuse large cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). The FDA has approved several CAR T cell therapies, including some approaches targeting CD19 (CART19) for adult and pediatric patients with B-cell malignancies. Response rates for CD19 CART therapy have been quite promising, reaching 80% overall response and 60% complete response; however, relapses are observed at an estimate of 30-40% within the first year. Thus, finding clinically translatable approaches to improve response rates for patients receiving CART19 therapies, such as the potential of LD-TBI, is critical. Multiple mechanisms of CAR T cell therapy resistance include limited persistence of the CAR T cell product upon infusion, CAR T cell exhaustion, and reduced or complete loss of target expression. Here, we will describe the significant role of radiation therapy, particularly low-dose total body irradiation (LD-TBI), in enhancing the long-term response of CAR T cell therapy. LD-TBI can modulate antigen stability, augment the expression of death receptors in tumor cells, and improve the persistence of CAR T cells. Moreover, LD-TBI also enhances lymphodepletion and the trafficking of CAR T cells to the tumor-infiltrated organs. As a result, LD-TBI significantly prolongs the survival of mice bearing lymphoma or B-ALL in combination with anti-CD19 CAR T cells, thereby improving patient outcomes and offering a promising future for cancer treatment. Citation Format: Monica L. Guzman. Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA07

Flow cytometry immunophenotyping in diagnosed cases of B-cell chronic lymphoproliferative disorders

Objectives Mature B-cell neoplasms consist of a diverse group of disorders with distinct clinical presentations, pathology, and outcomes. This article aims to describe the clinical, morphological, and flow cytometry immunophenotypic findings of 30 diagnosed patients with B-cell lymphoproliferative disorders (B-CLPDs) in a tertiary care hospital in Sri Lanka. Material and Methods A descriptive cross-sectional study, including 30 cases of BCLPDs diagnosed over a period of 6 months, was analyzed. Diagnosis of BCLPDs was made by morphology of peripheral blood, bone marrow, and the immunophenotypic analysis by multiparametric flow cytometry on bone marrow aspirates or peripheral blood. Results CD5-/CD10- BCLPD with negative hairy cell markers was the most common subtype (30%), followed by chronic lymphocytic leukemia (CLL) at 26.6% and mantle cell lymphoma (MCL) at 20%. Persistent lymphocytosis was the most frequent clinical finding across BCLPD cases, while hepatomegaly was common in the cases of the CD5-/CD10- BCLPD with negative hairy cell markers. This category appears distinct from other known subtypes like splenic marginal zone lymphoma (SMZL) or hairy cell leukemia (HCL), suggesting a unique clinical profile. Conclusion The study highlights distinct immunophenotypic and clinical profiles across BCLPD subtypes, with CD5-/CD10- BCLPD subtype with negative hairy cell markers emerging as the most prevalent and showing unique marker patterns that may aid in differential diagnosis.

CRISPR/Cas9-Enhanced CAR-T Cell Therapy for Hematological Malignancies

CRISPR/Cas9 technology has brought revolution to the field of gene editing, offering precise and efficient tools for genetic modifications. One of its most promising applications lies in improving CAR-T cell therapy for treating hematological malignancies. Among approaches to treating blood cancers, CAR-T therapy, which programs T cells to recognize and eliminate cancer cells, has shown some success for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (ALL). However, challenges such as immune evasion, cytokine release syndrome (CRS), neurotoxicity, and limited CAR-T persistence remain significant barriers. CRISPR/Cas9 can optimize CAR-T therapy by precisely inserting CAR genes into specific loci, knocking out inhibitory genes like PD-1 to enhance persistence, and enabling multi-targeting strategies to overcome tumor immune escape. Clinical trials demonstrate the feasibility and potential of CRISPR-edited CAR-T cells, showing improved safety, durability, and efficacy. This study explores the synergistic application of CRISPR/Cas9 in CAR-T therapy, addressing its current limitations and providing a pathway to safer and more effective treatments for hematological malignancies

Positron Emission Tomography Imaging and HScore-Based Diagnosis in Two Children with Malignancy-Associated Hemophagocytic Syndrome: Anaplastic Large-Cell Lymphoma and Precursor B-acute Lymphoblastic Leukemia.

Positron Emission Tomography Imaging and HScore-Based Diagnosis in Two Children with Malignancy-Associated Hemophagocytic Syndrome: Anaplastic Large-Cell Lymphoma and Precursor B-acute Lymphoblastic Leukemia.

New treatments for adult T-cell leukemia/lymphoma.

Adult T cell leukemia lymphoma (ATL) is a mature T cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). ATL is endemic in specific geographic regions of the world closely related to areas with high prevalence of HLTV-1 infection, including Southwestern Japan, the Caribbean Basin, Central Africa, South America, Northern and Central Australia. HLTV-1 is primarily transmitted through breastmilk in asymptomatic carriers with a long latency period before transformation into ATL in 3 - 5 % of carriers after acquisition of multiple leukemogenic mutations. The Shimoyama classification established by the Japanese Lymphoma Study Group more than three decades ago remains clinically relevant and practical for guiding treatment. Due to the rarity of this illness, prospective, large prospective clinical are challenging to perform and treatment recommendations are based upon limited evidence. Aggressive disease subtypes have median survival ranging in months and the only curative therapy remains achieving deep remission with induction therapy followed by consolidative allogeneic transplantation. The prognosis for relapsed disease remains dismal due to chemo-refractoriness and limited therapeutic options. Herein, we review the current landscape of novel therapeutic agents with a focus on relapsed and refractory ATL including their mechanisms of action, resistance, and clinical efficacy.

Relapsed childhood T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

While outcomes for pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) have improved dramatically in recent decades, relapsed and refractory disease remain a significant therapeutic challenge. This is particularly true for patients with T-cell ALL and LBL, where survival for patients with relapsed/refractory disease remains dismal. Recent efforts to comprehensively profile the genomics of T-ALL/LBL to improve understanding of disease biology have enhanced our ability to identify high-risk patients at diagnosis who are more likely to relapse and have also identified novel targets for precision medicines. Novel immunotherapies have transformed the treatment landscape for patients with B-cell ALL (B-ALL). Many immunotherapies are under investigation in clinical trials for patients with T-ALL/LBL and early results are very promising. Given these insights into disease biology and the development of targeted and immune-based treatments, it is reasonable to hope for improved patient outcomes, although challenges still exist. In this review, we summarize the present state of understanding of the risk factors for relapse of T-ALL/LBL, established treatment regimens, and the promising small molecule inhibitors and immunotherapies with the potential to revolutionize the treatment of relapsed/refractory T-ALL/LBL.

Outcome of critically ill patients receiving systemic chemotherapy on the intensive care unit.

Analyze the outcomes of critically ill patients who developed new-onset organ dysfunction and received systemic chemotherapy during their ICU stay. Retrospective cohort study. A tertiary medical center in Germany with an Intensive Care Medicine department consists of 11 intensive care units comprising 140 beds, serving all subspecialties of adult intensive care medicine. 167 patients receiving systemic oncological treatment from January 1st, 2015 to December 31st, 2021, with a data cut-off on December 31st, 2022. None. A total of 167 patients were included. The primary reasons for ICU admission were respiratory failure and shock/sepsis, each accounting for 34% of cases, while complications associated with oncological therapy accounted for less than 8%. The median age of hematological patients (n = 129) was 62 years (IQR 50-70), and for solid tumor patients (n = 38), it was 60 years (IQR 52-65). Predominant disease entities included lymphoma (43%) and acute myeloid leukemia (29%) among hematological patients, and lung cancer (47%) and gastrointestinal malignancies (17%) among solid tumor patients. Hematological patients had a significantly higher median Simplified Acute Physiology Score II (47 vs. 39 points; p=0.013), a higher need for invasive mechanical ventilation (59% vs. 50%; p=0.3), renal replacement therapy (54% vs. 24%; p < 0.001), and a higher 1-year mortality rate (64% vs. 53%; p=0.2) compared to solid tumor patients. The hazard ratio for 1 year survival for male sex was 2.34 (1.31-3.49), for mechanical ventilation 2.01 (1.33-3.04), for vasopressor therapy 1.98 (1.27-3.10), and for renal replacement therapy 1.51 (1.03-2.23), respectively. Administering intravenous chemotherapy in an ICU setting remains challenging, and the experience to establish an indication for systemic chemotherapy is still challenging. However, the study demonstrates that, after careful interdisciplinary decision-making, a substantial number of patients can benefit from it.

Incidence and impact of other malignancies after immunochemotherapy by fludarabine, cyclophosphamide, and rituximab as frontline treatment for chronic lymphocytic leukemia: A single-center retrospective study.

Individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have a high risk of developing other malignancies (OMs). The development of OMs may be associated with the advanced age of CLL/SLL patients, presence of a tumor-promoting microenvironment, immune alterations inherent to CLL/SLL, or chemotherapy. Importantly, the occurrence of OMs following frontline fludarabine, cyclophosphamide and rituximab (FCR) treatment is associated with a reduction in the overall survival (OS). This retrospective study included 108 CLL/SLL patients treated with FCR immunochemotherapy, as a first line treatment. With a median follow-up of 94.9 (6-222) months, 31% developed an OM or more, within a median of 61.8 months post-FCR initiation. The most common OMs were non-melanoma skin cancers (7%), Richter’s syndrome (RS) (7%), myelodysplastic syndromes (6%), prostate cancer (4%), and acute myeloid leukemia (3%). Patients with OMs had shorter survival compared to those without (104.0 versus 149.0 months, P=0.02), with RS having the worst OS at 4.8 months (P&lt;0.0001), followed by therapy-related myeloid neoplasia (t-MN) at 14.5 months. Although the onset of OMs in patients with CLL/SLL was observed after considerable delays, its impact on survival is significant in the immunochemotherapy era, necessitating a better understanding of these patterns to improve CLL/SLL management and guide future treatment strategies.

Serum NMR metabolomics in distinct subtypes of hematologic malignancies.

Hematologic malignancies encompass a diverse array of subtypes, contributing to substantial heterogeneity that poses challenges in predicting clinical outcomes. Leveraging the capabilities of nuclear magnetic resonance holds substantial promise in the detection of serum biomarkers and individual metabolic alterations in patients. This study involved the analysis of the sera from patients with acute myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma to investigate the affected metabolites and their associated pathways. The quantitative one-dimensional (1D) 1H nuclear magnetic resonance method was employed to identify alterations. Metabolite annotations were validated using two-dimensional (2D) analyses. Discriminating chemometric models and receiver operating characteristic curves were created using the MetaboAnalyst platform. The findings revealed significant alterations in the serum levels of amino acid catabolism products, citrate cycle intermediates, and phospholipids. The acute myeloid leukemia group showed differences in glucogenic amino acids related to the glycolysis pathway, whereas the chronic lymphocytic leukemia and non-Hodgkin lymphoma groups displayed variances in fumarate and acetate levels linked to the citrate cycle pathway. In the leukemia groups, higher levels of products from the protein degradation pathway were observed. The biomarker panels for each malignancy group exhibited outstanding discrimination from controls. Healthy individuals differed distinctly from patients, indicating commonly observed metabolic adaptation patterns among frequent hematologic malignancies. The small cohort study using nuclear magnetic resonance metabolomics in various hematologic malignancy subtypes revealed significant changes in serum amino acid and protein degradation end-product levels, suggesting prolonged leukocyte lifespan and increased energy demand.

New insights into mitochondrial quality control in anthracycline-induced cardiotoxicity: molecular mechanisms, therapeutic targets, and natural products.

Anthracyclines (ANTs) are widely used in cancer therapy, particularly for lymphoma, sarcoma, breast cancer, and childhood leukemia, and have become the cornerstone of chemotherapy for various malignancies. However, it is associated with fatal and dose-dependent cardiovascular complications, especially cardiotoxicity. Mitochondrial quality control mechanisms, encompassing mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, maintain mitochondrial homeostasis in the cardiovascular system. Recent studies have highlighted that mitochondrial quality control mechanisms play considerable roles in ANTs-induced cardiotoxicity (AIC). In addition, natural products targeting mitochondrial quality control mechanisms have emerged as potential therapeutic strategies to alleviate AIC. This review summarizes the types, incidence, prevention, treatment, and pathomechanism of AIC, delves into the molecular mechanisms of mitochondrial quality control in the pathogenesis of AIC, and explores natural products that target these mechanisms, so as to provide potential targets and therapeutic drugs for address the clinical challenges in AIC prevention and treatment, where no effective medicines are available.

Acute Neurotoxicity in Children Treated for Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: A 10-Year Single-Centre Experience.

Background: Recent advances in childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) management provide higher survival rates at the cost of increased toxicities. Acute neurotoxicity affects up to 10% of patients, requiring rapid recognition and treatment. Methods: A retrospective observational study was performed to determine the frequency, clinical manifestations, radiological characteristics, treatment options and outcome of acute neurological adverse events in pediatric patients with lymphoid malignancies at the Department of Oncology and Hematology, Children's Hospital Zagreb, Croatia. Results: A total of 56 patients (48 ALL and 8 LL, male/female ratio 1:1, average age 5.4 years) were treated mainly according to the ALL-IC BFM 2009 protocol. The B-immunophenotype was the most frequent (85.7%). Most patients were stratified to the intermediate risk group (39.3%), and two were initially diagnosed with central nervous system infiltration. Acute neurotoxic events were registered in 11 patients (19.6%), most commonly in the 6-10-year age group (66.7%), predominately in females (72.7%) and high-risk group (54.5%). The most frequent clinical presentation was seizures (83.3%), with status epilepticus in four cases. We detected electroencephalogram (EEG) irregularities in almost all patients and various morphological changes in the brain magnetic resonance imaging (MRI), most often consistent with posterior reversible encephalopathy syndrome and leukoencephalopathy. Approximately half the patients received prolonged antiepileptic therapy. No apparent residual neurologic manifestations have been observed. Conclusions: Acute neurotoxicity is a rather frequent treatment-related adverse event, associated with high-risk disease. Early recognition and timely management are essential for rapid recovery and optimal outcomes.

Underrepresentation of Small Lymphocytic Lymphoma in Clinical Trials for Chronic Lymphocytic Leukemia.

Although chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same biologic disease entity and warrant identical treatment approaches, patients with SLL have frequently been excluded from clinical trials in CLL. This study assessed the representation of patients with SLL among Phase II or III clinical trials cited in the 2024 National Comprehensive Cancer Network (NCCN) treatment guidelines. Patients with SLL were explicitly eligible for only 21 (38%) of the 56 clinical trials for CLL, comprising 222 (6%) of the 3440 enrolled patients. Notably, 380 patients with SLL were enrolled in 16 separate non-CLL clinical trials alongside patients with indolent B-cell lymphomas such as follicular lymphoma. In CLL trials, patients with SLL were included in a greater proportion of studies evaluating BTK inhibitors (67%) or BTK/BCL2 inhibitor combinations (67%) compared to BCL2 inhibitors (0%) or chemoimmunotherapy (0%). Although recent and upcoming trials show a promising trend toward the inclusion of patients with SLL, further advocacy is needed to raise awareness of the biological similarities between CLL and SLL and to promote the representation of patients with SLL in CLL/SLL clinical research.

A Single Centre Study of the Prevalence of Haematological Malignancies in the South-South Region of Nigeria

Background: Haematological malignancies are clonal haemopoietic disorders characterised by the accumulation of malignant haemopoietic cells in various body tissues. They arise due to varied genetic damages to several key biochemical pathways in cellular differentiation, proliferation and maturation. Objective: To determine the prevalence of haematological malignancies in Delta State, Nigeria. Methods: The study was a longitudinal study carried out at Delta State University Teaching Hospital, Oghara. Patients were recruited consecutively as diagnoses were made. Results: Seventy-three patients diagnosed with haematological malignancies were involved in this study. Females were slightly more affected than males (50.7% vs 49.3%), and patients of 40 - 65 years were most affected (28.8%). Non-Hodgkin Lymphoma (16.4%) and Chronic Lymphocytic Leukaemia (16.4%) were the most common haematological malignancies. More female had CLL (91.7%), Myelodysplastic syndrome (MDS) (57.1%), Acute Myeloid Leukaemia (AML) (100%) and Polycythaemia vera (PV) (100%). Conclusion: Haematological malignancies are common and on the rise in the centre of study and generally in Nigeria, with a notable change in the spectrum of the diseases.

Synthesis and Anti-Cancer Activity In Vitro of Synephrine Derivatives.

Glucocorticoids (GCs) are routinely used to treat hematological malignancies; however, long-term treatment with GCs can lead to atrophic and metabolic adverse effects. Selective glucocorticoid receptor agonists (SEGRAs) with reduced side effects may act as a superior alternative to GCs. More than 30 SEGRAs have been described so far, yet none of them reached clinical trials for anti-cancer treatment. In the present work, we propose a novel approach to increase the number of potential SEGRAs by obtaining derivatives of synephrine, a molecule of natural origin. We synthesized 26 novel compounds from the class of synephrine derivatives and characterized them by HRMS, and 1H and 13C NMR. We evaluated in vitro anti-cancer effects in leukemia K562 and lymphoma Granta cells using the MTT assay and studied their potential affinity for the glucocorticoid receptor (GR) in silico using the molecular docking approach. The novel derivative 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2) with the highest GR affinity in silico exhibited cytotoxic activity against K562 and Granta cells after 24 h of treatment at the concentration of approximately 13 µM which correlated with its highest MolDock Score. The other compound with high GR affinity, 2-(hexylamino)-1-(4-nitrophenyl)ethanol (13S-G2), demonstrated cytotoxicity in both cell lines at concentrations of 50-70 µM. Overall, our results may provide a solid rationale for developing and further investigating synephrine derivatives as SEGRAs with anti-cancer activity.

Novel 4-alkoxy Meriolin Congeners Potently Induce Apoptosis in Leukemia and Lymphoma Cells.

Meriolins (3-(pyrimidin-4-yl)-7-azaindoles) are synthetic hybrids of the naturally occurring alkaloids variolin and meridianin and display a strong cytotoxic potential. We have recently shown that the novel derivative meriolin16 is highly cytotoxic in several lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells and predominantly targets cyclin-dependent kinases (CDKs). Here, we efficiently synthesized nine novel 2-aminopyridyl meriolin congeners (3a-3i), i.e., pyrimeriolins, using a one-pot Masuda borylation-Suzuki coupling (MBSC) sequence, with eight of them bearing lipophilic alkoxy substituents of varying length, to systematically determine the influence of the alkoxy sidechain length on the biological activity. All the synthesized derivatives displayed a pronounced cytotoxic potential, with six compounds showing IC50 values in the nanomolar range. Derivatives 3b-3f strongly induced apoptosis and activated caspases with rapid kinetics within 3-4 h in Jurkat leukemia and Ramos lymphoma cells. The induction of apoptosis by the most potent derivative 3e was mediated by the intrinsic mitochondrial death pathway, as it was blocked in caspase-9 deficient and Apaf-1 knockdown Jurkat cells. However, as recently shown for meriolin16, derivative 3e was able to induce apoptosis in the Jurkat cells overexpressing the antiapoptotic protein Bcl-2. Since tumor cells often inactivate the intrinsic mitochondrial apoptosis pathway (e.g., by overexpression of Bcl-2), these meriolin congeners represent promising therapeutic agents for overcoming therapeutic resistance.

The survival grip-how cell adhesion promotes tumor maintenance within the microenvironment.

Cell adhesion is warranted by proteins that are crucial for the maintenance of tissue integrity and homeostasis. Most of these proteins behave as receptors to link adhesion to the control of cell survival and their expression or regulation are often altered in cancers. B-cell malignancies do not evade this principle as they are sustained in relapsed niches by interacting with the microenvironment that includes cells and their secreted factors. Focusing on chronic lymphocytic leukemia and mantle cell lymphoma, this Review delves with the molecules involved in the dialog between the adhesion platforms and signaling pathways known to regulate both cell adhesion and survival. Current therapeutic strategies disrupt adhesive structures and compromise the microenvironment support to tumor cells, rendering them sensitive to immune recognition. The development of organ-on-chip and 3D culture systems, such as spheroids, have revealed the importance of mechanical cues in regulating signaling pathways to organize cell adhesion and survival. All these elements contribute to the elaboration of the crosstalk of lymphoma cells with the microenvironment and the education processes that allow the establishment of the supportive niche.

Potassium/sodium cation carriers robustly up-regulate CD20 antigen by targeting MYC, and synergize with anti-CD20 immunotherapies to eliminate malignant B cells.

Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.