Efficacy of ABBV-MALT1 across non-GCB PDX models

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators—p300, BRD4, or CDK9—produce distinct genomic responses, suggesting specialized therapeutic uses.

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.

Efficacy of ABBV-MALT1 the OCI-LY10 CDX model

Abstract Diffuse large B cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous malignancy that can be classified into germinal center (GCB) and activated B cell (ABC) subtypes. Clinically, these subsets are often classified by immunohistochemistry (IHC) with CD10 and BCL6 expression being characteristic of GCB and IRF4 (MUM1) expression being characteristic of ABC. Efforts to inhibit signaling pathways active in ABC DLBCL by addition of targeted therapies to frontline chemoimmunotherapy have failed to meet their primary endpoints, and mechanisms of resistance to targeted therapies in DLBCL have not been extensively explored in clinically relevant models. Targeting BCL6 has recently emerged as an exciting therapeutic direction, with multiple BCL6 degraders now being tested in early phase clinical trials. BCL6-targeting transcriptional/epigenetic chemical inducers of proximity (TCIP) are an innovative approach to recruit transcriptional coactivators that flip BCL6 from a transcriptional repressor to an activator and induce the expression of its target genes. We thoroughly tested the efficacy of a TCIP that recruits BRD4 to BCL6-bound site (TCIP1) using our extensive PDX repository, evaluating models with uniformly high (n=5), heterogeneous (n=6) or negative (n=2) expression of BCL6 by IHC. PDX models with high BCL6 expression all responded rapidly to TCIP1, with eradication of tumors in 4/5 models including those from CAR T refractory tumors with p53 mutation. As expected, BCL6 negative models showed no response. Interestingly, BCL6 heterogeneous models also showed no response compared to vehicle control. Mechanistic studies by RNA-sequencing following short term in vivo exposure to TCIP1, its constituent components (BCL6 BTB binder; BRD4 binder) or vehicle control in BCL6 high (n=3) or heterogeneous (n=3) models revealed a selective up-regulation of IRF4 activity in BCL6 heterogeneous models. Evaluation by IHC showed that, at baseline, BCL6 heterogenous models consisted of mixed populations of BCL6+IRF4- and BCL6-IRF4+ cells that were polarized to a uniformly BCL6-IRF4+ state under TCIP1 pressure, then returned to heterogeneous states following secondary implantation. IRF4 can be indirectly targeted using lenalidomide (len), thus we evaluated the activity of TCIP1+len combination in two BCL6 heterogeneous models. Single agent TCIP1 or len treatment resulted in no significant reduction in tumor volume compared to vehicle control. However, TCIP+len drove significant in vivo responses. In conclusion, we present the first data implicating epigenetic mosaicism and plasticity as a resistance mechanism to targeted therapy in DLBCL. Using a large array of PDX models we show impressive efficacy for TCIP1 in BCL6 high DLBCL and identify a rational strategy to overcome escape via epigenetic plasticity using a combination of TCIP1 and lenalidomide to target polar epigenetic states. Citation Format: Haopeng Yang, Kevin Bowman, Wenzhi Ji, Sai Gourisankar, Ashley L. Wilson, Zihan Yang, Ethan Marszalek, Stephen M. Hinshaw, Tinghu Zhang, Xiaofan Liu, Andrey Krokhotin, Sabin Nettles, Suprateek Kundu, Gerald R. Crabtree, Nathanael S. Gray, Michael R. Green. Epigenetic rewiring of BCL6 drives responses and unveils synthetic dependencies in large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1844.

SET-domain containing protein 2 (SETD2) is the primary methyltransferase responsible for generating H3K36me3, an epigenetic mark that is essential for transcriptional regulation and chromatin integrity. SETD2 mutations are frequently observed in various cancers and tend to cluster within its catalytic SET domain. Despite the clinical relevance of SETD2 missense mutations in cancer, their biochemical and structural consequences remain insufficiently characterized. Here, we present the enzymatic and structural characterization of the SETD2 L1609P mutant enzyme identified in leukemia. The L1609 residue is located in the SET domain within a conserved hydrophobic pocket that is involved in substrate H3K36 recognition. Interestingly, site-directed mutagenesis of residues within this hydrophobic pocket leads to SETD2 enzyme variants with either decreased or increased H3K36me3 methyltransferase activity, suggesting that cancer mutations affecting the L1609 residue could result in a loss-or gain-of-function enzyme variant. Using molecular and cellular approaches, we show that the SETD2 L1609P mutant exhibits reduced H3K36 methyltransferase activity, decreased protein stability, and poor cellular expression. Consistently, the crystal structure of the SETD2 L1609P in complex with a H3K36M peptide shows remodeling of the active site. These findings support the pivotal role of SETD2 inactivation and subsequent disruption of H3K36me3 deposition in oncogenesis, particularly in hematologic malignancies. Our study provides the first mechanistic and three-dimensional protein structure information on how SETD2-associated cancer mutations can lead to altered H3K36 methyltransferase activity.

In vitro and in vivo combination of ABBV-MALT1 and venetoclax

Supplementary Materials and Methods

The clinical and molecular heterogeneity of diffuse large B cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic, and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features that span known molecular subtypes. PG4 is associated with poor outcome independent of established risk factors such as cell-of-origin, international prognostic index, or genetic features. PG4 contains activated B cell-like and germinal center B cell-like tumors and genetically unclassified cases. It shares a dark-zone-related B cell phenotype and shows enrichment for BTG1 mutations that can activate MYC. Single-cell sequencing and spatial transcriptomics reveal enhanced MYC and TCF3/4 transcriptional activity irrespective of MYC translocations. The PG4 tumor microenvironment is characterized by exhausted CD8+ T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.

Due to the rapidly evolving landscape of targeted therapies, there is an unmet need for comprehensive molecular profiling to guide treatment decisions for patients with large B-cell lymphoma (LBCL). Therefore, we designed a pilot study to assess the feasibility and turnaround time (TAT) of a comprehensive whole exome sequencing (WES) and transcriptome sequencing (RNA-seq) assay in patients with LBCL (NCT05464823). Patients aged ≥18 years with LBCL were eligible. Formalin-fixed paraffin-embedded tissues at diagnosis or recurrence underwent WES, RNA-seq, and copy number analysis with concomitant germline DNA sequencing. Genomic and transcriptomic data were profiled to define various LBCL signatures such as cell-of-origin (COO), dark zone signature (DZsig), LymphGen and lymphoma microenvironment (LME) classification. Among 100 patients enrolled, samples from 71 patients (48 with newly diagnosed and 23 with relapsed/refractory disease) passed pathology quality control and underwent WES and RNA-seq analysis and reporting. The median TAT was 8 days for individual patient reports (range: 6-22 days), with 73% of reports delivered ≤10 days. Applying molecular risk classification, high risk event-free survival within 24 months (EFS24) signature was associated with DZsig and LME, but not with COO or LymphGen indicating the complex heterogeneity of the disease. We demonstrated the clinical utility and acceptable TAT of a comprehensive WES and RNA-seq assay for LBCL managed in routine clinical practice. These findings support the real-world feasibility of using integrated WES and RNA-seq to define molecular subgroups, guide clinical decision-making at the time of a new line of therapy, and enable biology based subtype-driven clinical trials.

Approximately 30-40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) develop relapsed or refractory (r/r) disease after frontline therapy. Harnessing targetable biological vulnerabilities, the Smart Start trial served as a proof-of-concept for a frontline noncytotoxic combination regimen utilizing rituximab, lenalidomide and ibrutinib (RLI regimen) and demonstrated promising outcomes at initial follow-up. Herein, we present the updated analysis of the long-term outcomes of safety and efficacy of the Smart Start trial (PMID 35952327). Methods This was an investigator-initiated, open-label, single-center, phase II clinical trial investigating pts with untreated non-germinal center B-cell (non-GCB) DLBCL. Pts received two cycles of RLI (rituximab 375 mg/m2 IV day 1, lenalidomide 25 mg daily orally days 1-10, ibrutinib 560 mg orally daily; pts>65 years (yrs) could receive ibrutinib 420 mg per amended protocol) followed by chemotherapy (R-CHOP or R-EPOCH) for cycles 3-8 along with continued RLI. Results 60 pts were enrolled from May 2016 until February 2019. The median age was 63.5 yrs, with 28% of pts being older than 70 yrs, and 42% (25/60) considered poor risk per Revised International Prognostic Index. The median time from diagnosis to treatment was 28 days (range, 9-138 days). Two pts withdrew consent prior to starting therapy and were only evaluable for safety. Two pts only received two cycles of RLI-alone; one withdrew consent after a complete response (CR) and one due to progression of disease (PD) and central nervous system aspergillosis. Fifty-six pts received RLI combined with chemotherapy (EPOCH: n=31; CHOP: n=25). Of note, one pt had preplanned radiation to the contralateral testicle after completing study therapy with a CR, and one patient switched from EPOCH to RCHOP based on treating physician preference. With a median follow-up of 77.1 months (range, 2.4-103.0), the median progression-free survival (PFS) and overall survival (OS) were not reached. At 6-yrs, PFS was 84% (95% CI, 74-94%), and OS was 91% (95% CI, 84-99%). A total of six death events occurred - three additional deaths since the original publication. Three of six deaths were determined to be lymphoma-related, either secondary to PD (n=1) or infectious complications in the setting of treatment (n=2). The remainder (n=3) were secondary to metastatic breast cancer (n=1) and unknown causes (n=2). Seven pts were determined to have PD during the updated entire follow-up period. Most events occurred early (<2 yrs after treatment), while two PD events occurred at 47 and 70 months. Pathology results (available in four pts) demonstrated a r/r B-cell lymphoma (BCL) in all pts (high-grade BCL: n=1; GCB BCL with anaplastic features: n=1; non-GCB DLBCL: n=1; BCL, not otherwise specified: n=1). One pt who received only 2 cycles of RLI-alone remains in CR after 86 months. Among five pts with treatment details available after PD, three pts received autologous stem cell transplant, and two pts received a CD19-directed chimeric antigen-receptor T cell therapy. On safety analysis, the most common adverse events during treatment included nausea (all grades: 85%, grade ≥3: 3%), peripheral sensory neuropathy (all : 83%, grade ≥3: 8%), diarrhea (all grades: 78%, grade ≥3: 13%) and mucositis (all grades: 75%, grade ≥3: 3%). Furthermore, the most common grades 3 or higher were neutropenia (53%), thrombocytopenia (47%) and anemia (38%). Febrile neutropenia occurred in 37%. No new long-term safety signals were observed from the addition of RLI. Two pts developed reduced ejection fraction heart failure, attributed to anthracycline exposure (n=1) and atherosclerotic coronary artery disease (n=1). Furthermore, one pt developed chronic phase chronic myeloid leukemia. Conclusion This updated analysis of the Smart Start trial establishes the robust long-term safety and durability of incorporating RLI into the frontline treatment of pts with newly diagnosed DLBCL. Although direct comparisons cannot be made, numerically improved survival outcomes were observed compared to historical cohorts treated with R-CHOP alone (GOYA trial - 5-year PFS of 62.6% and OS of 77.7%; Sehn et al, 2020). These promising findings indicate that the integration of innovative targeted therapy strategies for the frontline management of DLBCL should be assessed in larger, later-phase trials.

MALT1 and BCL2 inhibition do not antagonize each other in monotherapy sensitive patient derived xenografts

Large B-cell lymphomas (LBCL) are a clinically and molecularly diverse group of malignancies with a rapidly evolving therapeutic landscape that has introduced new areas of clinical need, such as post-CD19 chimeric antigen receptor T (CART19) progression. Patient-derived xenograft (PDX) models are an important tool for mechanistic studies and preclinical evaluation of new therapies and can be generated from a variety of clinical contexts that capture tumor-intrinsic resistance mechanisms. We therefore undertook a comprehensive effort to generate PDX models that encompass the molecular landscape of LBCLs and include important clinical scenarios for new drug development. Here, we describe the first 48 models within this publicly available repository, capturing the transcriptional and genetic subsets of LBCL. These models also include 23 generated from post-CART19 progression patient biopsies, which reproduce patterns of progression driven by CD19 mutation or expression loss, as well as tumor cell-intrinsic CART19 resistance that we validated in vivo. SIGNIFICANCE:Here, we describe X-LYMPH (Xenografts of Lymphoma), a publicly available and molecularly annotated PDX repository that captures the heterogeneity of LBCL. X-LYMPH includes models of CAR T-cell resistance, providing a shared foundation for mechanistic research and therapeutic development for lymphomas. See related commentary by Evgin and Steidl, p. 655.

Mantle cell lymphoma (MCL) is one of the deadliest forms of Non-Hodgkins B-cell lymphoma. Typically, patients present with both overexpression of CyclinD1 and secondary mutations identified by genomic sequencing. Although MCL patients may initially respond to treatment, they eventually relapse and succumb to disease, highlighting the essential need to identify new targets for treatment. Here we performed proteomic profiling of healthy B cells and three different forms of B-cell malignancies, including MCL, to define the proteomic signature of MCL. We compared the proteome of each to MCL and identified 10 proteins that are specifically upregulated in MCL. Of these 10 proteins, seven of them show no transcriptional changes and have been overlooked by conventional RNA expression analysis. Further analysis of the proteomic signature reveals potential avenues for dual targeting in CAR T-cell therapy and provides guidance for personalized therapeutics based on protein expression.

Abstract Intratumoral heterogeneity in the spatial arrangement of phenotypically distinct tumor subpopulations is increasingly recognized, yet whether spatial topology independently determines clinical outcomes and reflects distinct biological programs remains unclear. Using diffuse large B-cell lymphoma (DLBCL) as a model, we reported (AACR 2025) that the spatial distribution of MYC+BCL2+BCL6- double expressor (DE) cells — quantified by point process modeling of multiplex immunohistochemistry (mIHC) across 476 patients in four independent cohorts — independently predicts survival after chemoimmunotherapy, and identified a transcriptional signature of dispersed DE cells associated with inferior outcomes in gene expression cohorts (4,594 patients). The mechanistic basis for why genotypically identical MYC+BCL2+ cells adopt distinct spatial configurations with divergent clinical impact is unknown. Given that MYC-driven ribosome biogenesis (RiBi) normally triggers the impaired RiBi checkpoint (IRBC), wherein the RPL5/RPL11/5S rRNA complex binds and inhibits MDM2 to stabilize p53, we investigated whether this prognostic spatial signal reflects differential IRBC engagement. Using single-cell RNA-sequencing in de novo (n=17) and relapsed/refractory (R/R; n=99) settings and digital spatial profiling (GeoMx DSP-WTA, n=64), we found that although cells with dispersed and clustered signatures both upregulated RPL5 under MYC-driven ribosomal stress, dispersed DE cells selectively evaded IRBC engagement: they exhibited elevated MDM2 expression, reduced p53 stabilization, and diminished p53 transcriptional activity, conserved across de novo and R/R contexts and independent of TP53 mutation status. We postulate that NF-κB pathway activation in dispersed DE cells transcriptionally drives MDM2 overexpression sufficient to overwhelm RPL5/RPL11-mediated inhibition, establishing a feed-forward loop: sustained MDM2 activity inactivates p53, which normally suppresses NF-κB, thereby promoting PTGES3-mediated prostaglandin E2 (PGE2) synthesis. Cell-cell communication analysis confirmed enriched PGE2 signaling in dispersed versus clustered configurations across both disease settings. Critically, hyperplex spatial proteomics (PhenoCycler, n=152) revealed that dispersed DE cells, despite significantly greater spatial proximity to T cells than clustered counterparts, orchestrated a profoundly immunosuppressive niche characterized by regulatory T cell enrichment and terminal CD8+ T cell exhaustion — a spatial immune phenotype consistent with tumor-derived PGE2-mediated suppression of anti-tumor effector responses and conserved across de novo and R/R disease. These findings establish IRBC avoidance as a spatially determined mechanism of non-mutational p53 inactivation in MYC-driven lymphoma and identify the p53-NF-κB-PGE2-T cell exhaustion axis as a potential therapeutic vulnerability in spatially dispersed double expressor DLBCL. Citation Format: Shruti Sridhar, Charmaine Ong, Chartsiam Tipogamut, Qiang Pan Hammarström, Kasthuri Kannan, David W. Scott, Xubin Li, Michael R. Green, Claudio Tripodo, Anand D. Jeyasekharan. Spatially dispersed MYC-BCL2 co-expressing cells confer poor survival in DLBCL through functional p53 loss and PGE2-mediated immune evasion [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 A051.

Abstract Cancer therapies that activate cell death are critical to avoid relapse. Approximately 30% of diffuse large B cell lymphoma (DLBCL) cases, the most common non-Hodgkin lymphoma, fail standard-of-care treatment regimens, highlighting the need for new death-promoting targeted therapies. Here, we introduce a gain-of-function small molecule modality that kills DLBCL cells at sub-nanomolar potency (IC50 = 0.8 nM) through induced proximity. These bivalent compounds, Lysine Acetyltransferase Transcriptional/Epigenetic Chemical Inducers of Proximity (KAT-TCIPs), leverage the endogenous activity of the co-activating KATs E1A Binding Protein p300 (p300) and CREB-Binding Protein (CBP) to drive the transcription of death-promoting genes normally repressed by oncogenes. Specifically, KAT-TCIPs recruit p300/CBP to genomic loci controlled by the master transcriptional repressor BCL6, dysregulated in ∼40% of DLBCL cases, and rapidly reprogram the epigenome to promote BCL6-dependent cell cycle arrest and apoptosis. We report the first X-ray co-crystal structure of a TCIP molecule bound to p300 and BCL6, which guided the optimization of our lead KAT-TCIP, TCIP3. Additional biophysical characterization of TCIP3 revealed its function as a molecular glue that cooperatively seeds ternary complexes on chromatin. This compound exhibits robust preclinical efficacy in vivo. It ablates germinal center B cells, which are naturally enriched for BCL6 expression, in immunized mice (5 mpk bid dosed intraperitoneally) relative to vehicle controls. Additionally, TCIP3 eliminates tumors in DLBCL cell line-derived xenograft models within 11 days at the same dose. Notably, this molecule spares healthy lymphocytes and fibroblasts in cytotoxicity analyses. Collectively, our findings establish KAT-TCIPs as powerful tools for co-opting the malignant function of oncogenic drivers to activate robust cell death, with implications for precision epigenetic therapies. Citation Format: Meredith Nicole Nix, Sai Gourisankar, Sabin Nettles, Kevin Bowman, Haopeng Yang, Brendan G. Dwyer, Roman C. Sarott, Hind Abuzaid, Michael Martinez, Andrey Krokhotin, Lei Chen, Mark M. Davis, Daniel Fernandez, Tinghu Zhang, Michael R. Green, Stephen M. Hinshaw, Nathanael S. Gray, Gerald R. Crabtree. A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3981.

Aberrant epigenetic modification is one of the characteristics of the cancer genome. DNA hypermethylation of cytosine-phospho-guanine (CpG) islands, a hallmark of cancer cells, is well-studied and contributes to cancer development by silencing tumor suppressor genes. However, the mechanisms and biological significance of global DNA hypomethylation in cancer are still unclear. Here, using the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E knock-in mouse models, we demonstrate that endogenous expression of oncogenic BRAFV600E in non-transformed cells promotes global DNA hypomethylation by increasing the levels of ten-eleven translocation 3 (TET3), which converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). Furthermore, TET3 is targeted for proteasomal degradation by F-box and WD repeat domain containing 7 (FBXW7). BRAFV600E increases TET3 levels by inhibiting glycogen synthase kinase 3β (GSK3β), which phosphorylates TET3 and leads to its ubiquitination and proteasomal degradation. We further found elevated levels of TET3 and 5-hmC in BRAFV600E-induced mouse lung tumors and show that TET3 enhances the ability of BRAFV600E to induce the formation of lung tumors. Notably, endogenous expression of oncogenic Kirsten rat sarcoma virus (KRAS) G12D also promotes global DNA hypomethylation and induces lung tumors through a similar TET3-mediated mechanism. Our findings elucidate one of the unknown mechanisms of global DNA hypomethylation promoted by oncogenic BRAF and KRAS and establish a role for TET3 to promote transformation in cooperation with BRAF and KRAS at an early stage of tumorigenesis.

Pan-lineage PRISM analysis of ABBV-MALT1 sensitivity.

Although previous studies have examined the drug development and clinical trial success rates in oncology, a comprehensive analysis of development success rate in lymphoma has not been performed. Therefore, we analyzed lymphoma trials initiated between 1 January 2000 and 31 December 2019, using the Trialtrove database and ClinicalTrials.gov. We identified phase 1, 2, and 3 trials that included patients with lymphoma and analyzed the transition rate of investigational agents across phases and their US Food and Drug Administration (FDA) approval rates to assess the efficiency and success of the clinical development process. A total of 1032 phase 1 trials and 510 phase 1/2 trials were conducted, with a total of 651 distinct agents being evaluated during the study period. There were 1027 phase 2, 20 phase 2/3, and 140 phase 3 trials conducted for lymphoma, with 200 agents proceeding from phase 1 to 2 and 46 agents proceeding from phase 2 to 3. The success rates of agents proceeding from phase 1 to 2 and phase 2 to 3 were 30.7% and 23.0%, respectively. A total of 40 agents reached FDA approval, with an overall approval rate of 6.1%. The average time from initiation of the first phase 1 trial to approval for lymphoma treatment was 7.9 years. Our study characterizes the clinical development landscape and timeline of novel therapies for lymphoma. Low approval rate from phase 1 trials in lymphoma suggests the need for improvement in trial design and in prediction of clinical response through preclinical studies to improve the likelihood of success.

Antiapoptotic complex formation in ABC-DLBCL xenografts after ABBV-MALT1 monotherapy