Citations

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A049.

Abstract Background: Antigen receptor stimulation induces assembly of the CARMA1-BCL10-MALT1 (CBM) signaling complex, which leads to activation of downstream transcriptional regulators including NF-κB and subsequent lymphocyte activation. Gain-of-function mutations in B-cell receptor subunits, CARMA1, or BCL10 which lead to constitutive activation of MALT1 underly the pathogenesis of multiple lymphoid malignancies, including activated B-cell–type diffuse large B-cell lymphoma (ABC-DLBCL). During previous efforts to identify regulators of MALT1 activity in lymphocytes, we discovered that G-protein-coupled receptor kinase 2 (GRK2) binds to MALT1, inhibits MALT1 scaffolding and proteolytic activities, and functions as a tumor suppressor in MALT1-dependent lymphomas. Notably, GRK2 mRNA expression is markedly lower in a subset of DLBCL tumors in comparison to normal B cells and lower GRK2 is associated with decreased patient survival in ABC-DLBCL. In light of these findings, we investigated the molecular mechanisms regulating GRK2 expression and then characterized the roles of specific GRK2-targeting miRNAs in ABC-DLBCL. Methods and Results: After finding that global impairment of miRNA processing through DICER1 depletion leads to increased GRK2 protein, we conducted bioinformatic analyses of patient tumor samples and microRNA Data Integration Portal screening to identify candidate microRNAs that target GRK2 in ABC-DLBCL. Direct targeting of GRK2 by candidate miRNAs was then confirmed by GRK2 3’UTR reporter assay. We tested for expression of three candidate microRNAs in ABC-DLBCL cells and observed elevated expression in both OCI-LY3 and TMD8 cells, which exhibited reduced GRK2 mRNA expression compared with primary B cells. Inhibition of candidate miRNAs in ABC-DLBCL cells, using anti-miRNA Locked Nucleic Acids (LNA) inhibitors, led to enhanced GRK2 expression, reduced MALT1 activity and decreased cell proliferation. Conversely, stable overexpression of candidate microRNAs led to reduced GRK2 expression, enhanced MALT1 activity and increased cell proliferation. In vivo, treatment of mice with inhibitors of candidate microRNAs abrogates the growth of ABC-DLBCL xenograft tumors. Conclusion: We have identified three miRNAs that negatively regulate GRK2 expression in ABC-DLBCL. By targeting GRK2 for downregulation, these miRNAs promote MALT1 oncoprotein scaffold and protease activities. Furthermore, inhibitors of these miRNAs enhance GRK2 expression and thereby suppress MALT1 activity and MALT1-dependent tumor cell proliferation in vitro and inhibit MALT1-dependent tumor growth in vivo. MicroRNA inhibitors that enhance GRK2 expression could represent a new approach for restraining MALT1-dependent lymphoma. Citation Format: Jing Cheng, Mei Smyers, Matt Trotta, Neil M. Carleton, Lisa M. Maurer, Uma R. Chandran, Min Xia, Ari M. Melnick, Peter C. Lucas, Linda M. McAllister-Lucas. Inhibitors of GRK2-targeting-microRNAs: New therapeutic strategies for MALT1-dependent lymphomas [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A033.

ABSTRACT Palliative care can be offered concurrently as a treatment option to patients with pulmonary arterial hypertension (PAH) to relieve symptoms and improve quality of life. However, it is infrequently used and is associated with misconceptions. Limited studies have reported patients' perspectives of palliative care as a treatment option for PAH. We conducted a web‐based survey, informed by a brief targeted literature review and input from patients and clinicians, which was completed by adults (≥ 18 years) in the United States (US) with self‐reported PAH. Patients reported demographic and disease variables and their perspectives and experiences with palliative care. Patients self‐reported their Pulmonary Hypertension Functional Class Self‐Report class, EmPHasis‐10, and 6‐min walk test. A total of 200 respondents (86.5% female; mean age 58.5 years) from 42 US states completed the survey between 19 September and 3 October 2023. Most respondents described palliative care as “end‐of‐life care” ( n = 43, 25.7%) and associated it with the need for extra support ( n = 111, 55.5%). Many respondents ( n = 171, 85.5%) had not discussed palliative care services, nor had a palliative care consultation with their healthcare provider (HCP); most had not been offered a consultation ( n = 109/171, 63.7%). Despite this low frequency of discussions, respondents reported feeling comfortable discussing palliative care with their HCPs ( n = 177, 88.5%). The survey results demonstrated that these patients with PAH had limited experiences with palliative care, where palliative care was frequently subject to misinterpretation. These findings emphasize the need for proactive engagement between patients and HCPs to ensure palliative care is optimally used and understood.

Background: Anaplasmosis is an emerging tick-borne infection that typically presents as a non-specific febrile illness, with variable degrees of cytopenias and liver tests abnormalities. Severe complications remain atypical and uncommon. Case Report: We report a case of acute pulmonary embolism (PE) occurring during confirmed anaplasmosis in a 73-year-old male with no traditional thromboembolic risk factors. The patient presented with fever, constitutional symptoms, thrombocytopenia, leukopenia, and abnormal liver tests, raising suspicion for a tick-borne illness. Despite early clinical improvement on doxycycline, persistent tachycardia triggered further evaluation and uncovered an acute PE. Comprehensive workup at admission and repeated 14 months later excluded inherited and acquired thrombophilias, malignancies, autoimmune diseases, and alternative infectious etiologies. The patient was treated with doxycycline 100 mg orally twice daily for 10 days and anticoagulation with unfractionated heparin followed by 6 months of apixaban for a first episode of provoked PE. He attained complete clinical recovery without recurrence of thrombosis at the two-year follow-up. Discussion: Infectious diseases are increasingly recognized as contributors to thrombosis through inflammation-mediated hypercoagulability and endothelial dysfunction. Pulmonary involvement in anaplasmosis typically manifests as pneumonitis, pneumonia or acute respiratory distress syndrome, but thrombotic complications such as PE are exceedingly rare. This case highlights a rare but clinically significant vascular complication of anaplasmosis and underscores the importance of considering thromboembolic events in patients with persistent or unexplained tachycardia. Conclusions: As the incidence of anaplasmosis continues to rise, greater awareness of its potential cardiovascular manifestations is essential. Early recognition and prompt treatment with doxycycline remain critical, while further studies are needed to better define the thrombotic risk associated with this infection.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

ABSTRACT Glioblastoma (GBM) is universally lethal despite decades of research to find effective treatments. This highlights the need to identify druggable targets essential for sustaining the malignant phenotype but dispensable for normal tissue. We propose that the enzyme α-tubulin acetyl transferase ( ATAT1 ) meets these criteria. ATAT1 acetylates α-tubulin at lysine 40, which increases microtubule stability and promotes microtubule-based transport. While ATAT1 knockout mice have only a very mild phenotype, ATAT1 suppression in GBM has multiple therapeutic effects by reducing tumor invasion, proliferation, and therapeutic resistance. These translate not only into improved survival with ATAT1 targeting by itself, but also into synergy when ATAT1 deletion is combined with FDA approved therapies. This study strongly supports our conclusion that ATAT1 is a promising therapeutic target in GBM.

Abstract Multiple myeloma (MM) is a heterogenous cancer that remains mostly incurable. A unifying feature of MM cells is a highly interconnected network of transcription factors and co-factors that coordinate the activity of super-enhancers to enforce myeloma cell identity. Targeting this network offers a promising avenue for therapeutic intervention across genetically diverse myeloma sub-types. Using integrated molecular and functional genomic approaches we identified Menin as a key driver of oncogenic gene expression in MM cells. Menin and its co-factor KMT2A bind at super-enhancers and maintain expression of essential myeloma genes, including IRF4. We demonstrate that Menin inhibitors, which have recently been approved for treatment of acute myeloid leukaemia, are highly active in myeloma cell lines and in vivo models. Combining Menin inhibitors with other super-enhancer targeting therapies such EP300/CREBBP inhibitors or immunomodulatory drugs (IMiDs) overcomes epigenetic plasticity in cells resistant to single agent treatment.

Artificial intelligence (AI) is now applied across oncology, including imaging, pathology, therapy selection, toxicity assessment, and survival modeling, and large language models (LLMs) have been adopted particularly quickly. Reported physician use of AI roughly doubled between 2023 and 2026. The frameworks used to evaluate these tools have not advanced at the same rate. Many are available, but each was designed for a single stage of the AI lifecycle, and none directly answers the question most relevant to a treating clinician: whether a given tool is appropriate for the individual patient under care. We reviewed the frameworks in current use, including TRIPOD+AI, PROBAST+AI, CLAIM, SPIRIT-AI, CONSORT-AI, DECIDE-AI, MINIMAR, and CREMLS, together with the oncology-specific ESMO EBAI and the newer LLM-specific guidance (TRIPOD-LLM, MI-CLEAR-LLM, CHART, and ESMO ELCAP). Each addresses part of the evaluation problem, but none is sufficient on its own for oncology, where the standard of care changes rapidly, assays drift, biomarker-defined subgroups are small, and a model validated in one period may perform poorly in the next. LLMs introduce additional challenges, including sensitivity to prompting, undisclosed vendor updates, behavioral drift, and hallucination rates approaching 50% on clinical quality-assurance tasks. The predictive-model frameworks were not designed to capture these failure modes. The central argument of this review is that the frameworks the field requires already exist; what is missing is their mandatory adoption. We propose that journals and regulators move from recommending these frameworks to requiring their use, and we outline a cancer-aware evaluation pathway together with the specific responsibilities of authors, reviewers, journals, and regulators in implementing it.

Abstract Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.