CAR-T cell therapy is effective in hematologic malignancies but remains challenging in solid tumors owing to antigen heterogeneity and tumor microenvironment-induced exhaustion. Here, gene editing of the nuclear receptor NR2F6 restores CAR-T cell functionality, sustaining a TCF1⁺ progenitor-exhausted phenotype, enhancing metabolic fitness, and preserving cytotoxic potency under chronic antigen exposure. In immunocompetent models, Nr2f6-deficient CAR-T cells suppress solid tumor growth and induce robust, polyclonal host antitumor responses that persist after CAR-T clearance, as demonstrated by tumor re-challenge protection. Although infused CAR-T cells disappear within 2 weeks, durable tumor control coincides with epitope spreading and secondary immune responses, likely via dendritic cell reactivation. Protection against antigen-negative tumors and transferable immunity reveal a dual mode of direct cytotoxicity followed by durable immune reprogramming. This broadened host immunity may offset immune escape driven by antigen heterogeneity or loss, establishing NR2F6 inhibition as a promising CAR-T engineering strategy for durable, antigen-agnostic solid-tumor immunotherapy.

Abstract Extramedullary acute myeloid leukemia (eAML) represents a clinically challenging manifestation of acute myeloid leukemia (AML), but its molecular drivers remain poorly defined. We performed targeted sequencing in 85 eAML biopsies, representing one of the largest molecular analyses of eAML to date. We detected mutations in RAS or RAS -modifying genes ( RAS MUT ; NRAS, KRAS, PTPN11, CBL , and NF1 ) in 41% of cases, representing a significant enrichment compared to bone marrow (BM) samples of more than 1300 AML patients not selected for eAML. Analysis of paired eAML and BM specimens revealed expansion and/or de-novo appearance of RAS MUT clones at the extramedullary site. Functional studies using primary murine leukemia cells and CRISPR/Cas9-engineered isogenic human leukemia cell lines demonstrated that RAS MUT increase the migration and invasion of leukemic cells compared to RAS -wildtype controls. Consistently, RAS MUT cells showed increased infiltration into the chorioallantoic membrane of chicken embryos and demonstrated enhanced extramedullary growth after injection into immunocompromised mice. RNA sequencing revealed increased expression of junctional adhesion molecule-like ( JAML ) and activation of PI3K/AKT signaling in RAS MUT cells. JAML silencing and pharmacologic AKT inhibition reversed the RAS MUT -driven effects on leukemic cell migration, demonstrating a causal role of the JAML-PI3K/AKT axis in RAS MUT -driven eAML formation. In conclusion, these findings delineate the molecular landscape of extramedullary AML and show that RAS MUT are enriched within this AML subform. They further demonstrate that RAS MUT actively contribute to leukemic tissue infiltration through activation of a RAS MUT -JAML-PI3K/AKT axis, highlighting AKT signaling as a potential therapeutic vulnerability in RAS MUT -associated eAML.

Background:HER2 exon 20 insertions are rare oncogenic driver mutations in non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has proven efficacy in pretreated metastatic HER2-mutant NSCLC. However, its use as first-line therapy in oligometastatic settings remains undocumented. Case Presentation:A 66-year-old female presented with a right hilar lung mass and a singular symptomatic left frontal brain metastasis. Biopsy confirmed poorly differentiated adenocarcinoma (TTF-1 positive, PD-L1 TPS 0%) with an ERBB2 exon 20 insertion (p.Y772_A775dup). The patient declined standard chemo- and immunotherapy. An individualized treatment plan was developed, initiating off-label first-line T-DXd after resection and consolidating radiotherapy of the affected cerebral region. After four cycles of T-DXd, imaging demonstrated significant tumor reduction. Subsequent surgical resection of the primary tumor revealed a complete pathological response (ypT0N0, R0). Adjuvant T-DXd therapy was continued thereafter. Conclusion:This case illustrates the high efficacy of T-DXd as the sole first-line treatment in oligometastatic HER2-mutant NSCLC. Prospective studies are needed to systematically explore the efficacy and safety of this approach.

Background Human metapneumovirus (hMPV) is an increasingly recognized respiratory pathogen in immunocompromised patients, but its impact in haematological malignancies is poorly defined. Unlike influenza or SARS-CoV-2, hMPV has no specific treatment or vaccine, contributing to underdiagnosis and underestimation of its clinical relevance.Method We performed a multicentre retrospective cohort study within the Epidemiology of COVID-19 in patients with hematological malignancies: A European Haematology Association Survey/ Epidemiology of respiratory viral infections in patients with hematological malignancies: A European Haematology Association Survey registry of haematological patients with hMPV (January 2023-December 2024), comparing clinical features and outcomes with matched influenza and SARS-CoV-2 cohorts.Results The study included 130 patients with hMPV. Median age was 58.5 years; 57% were male. Plasma cell neoplasms (25%), lymphoma (23%), and acute myeloid leukemia (20%) were the most common hematological malignancies. Hospitalization occurred in 64%, intensive care unit (ICU) admission in 19%, and 30-day mortality was 8%. Most cases (73%) received supportive care only. Secondary infections were common (24%). Chronic renal disease significantly increased mortality risk (hazard ratio 20.9 11.05, P = .014). Compared with influenza and SARS-CoV-2, hMPV patients had comparable severity and outcomes, with 18.5% ICU admission rates versus 25.9% for influenza (P = .316) and 20.9% versus 4.7% for SARS-CoV-2 (P = .006), and 30-day mortality of 5.6% versus 11.1% for influenza (P = .489) and 7.0% versus 2.3% for SARS-CoV-2 (P = .277), yet received fewer targeted interventions.Conclusions hMPV causes clinically significant disease in patients with hematological malignancy, often necessitating hospital and ICU care, and leading to mortality. In the absence of specific treatments or vaccines, this virus remains an underrecognized pathogen in patients with hematological malignancy. Enhanced clinical awareness and investment in diagnostics, prevention, and therapeutics are needed.

Bridging therapy is commonly administered prior to B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory multiple myeloma (RRMM) to maintain disease control during the manufacturing period. However, the optimal choice and intensity of bridging therapy remain unclear, and it is debated whether outcomes are primarily influenced by bridging strategy or underlying disease biology. We aimed to evaluate the impact of different bridging strategies on outcomes after BCMA-directed CAR-T cell therapy in RRMM, while accounting for disease biology, response prior to infusion, and baseline hematopoietic reserve. This retrospective multicenter real-world study included 90 consecutive patients with RRMM treated with BCMA-directed CAR-T cells (idecabtagene vicleucel or ciltacabtagene autoleucel) in Austria between January 2024 and July 2025. Bridging approaches were categorized as polychemotherapy (PCHT), talquetamab-based regimens (Tal), or other strategies. Survival outcomes were estimated using the Kaplan-Meier method, and factors associated with progression-free survival (PFS) were analyzed using univariable and multivariable Cox proportional hazards models. Logistic regression models were applied to assess associations with early toxicity. After a median follow-up of 9.9 months, estimated median PFS was 17.1 months. In unadjusted analyses, PCHT was associated with inferior PFS compared with other bridging approaches. However, this association was not retained after adjustment for extramedullary disease/plasma cell leukemia (EMD/PCL) and International Myeloma Working Group high-risk status. CAR-T product type and number of prior lines of therapy showed no effect on PFS. EMD/PCL emerged as the strongest independent predictor of inferior PFS in multivariable analysis (adjusted hazard ratio 4.85), whereas International Myeloma Working Group high-risk status was not independently prognostic. In a secondary model, achieving at least a very good partial response prior to CAR-T infusion was associated with a trend toward improved PFS but did not reach statistical significance. Talquetamab-based bridging was associated with numerically favorable PFS without increased toxicity. The CAR-HEMATOTOX score independently predicted inferior PFS. Importantly, PCHT was not associated with higher CAR-HEMATOTOX scores, prolonged cytopenia, increased infectious complications, or lower ALC levels as a surrogate for CAR-T expansion. In this nationwide real-world analysis, disease biology-particularly the presence of EMD/PCL-was the dominant determinant of outcome after CAR-T cell therapy, outweighing the impact of bridging strategy. These findings suggest that inferior outcomes observed after intensive bridging are largely driven by adverse baseline disease characteristics rather than treatment-related effects, supporting a biology-adapted approach to bridging and emphasizing the importance of achieving optimal disease control prior to CAR-T infusion.

B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cells have revolutionized the treatment of relapsed/refractory multiple myeloma. However, no randomized head-to-head comparison of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) is available, and real-world data suggest differences in efficacy and toxicity. We performed a nationwide retrospective real-world analysis (RWA) of Austrian patients treated with ide-cel or cilta-cel between January 2024 and July 2025. Ninety patients were included, with largely balanced baseline characteristics and frequent high-risk features. Bridging therapy was administered to 94.4% of patients, resulting in high response rates prior to lymphodepletion. After a median follow-up of 17.6 months, no early separation of the progression-free survival (PFS) curves was observed between CAR-T products. Multivariable analyses showed a trend towards improved PFS with cilta-cel, whereas true extra-medullary disease (EMD) and prior bispecific antibody treatment before T-cell apheresis were associated with inferior PFS. Although previous RWA have demonstrated an early divergence in PFS between cilta-cel and ide-cel, this pattern was not observed in our cohort. The high effectiveness of bridging therapy may have contributed to these findings. Our results support further investigation of optimal bridging strategies and treatment sequencing while highlighting the persistent unmet need of patients with true EMD.

The recently published ONKOPEDIA guideline on myelofibrosis, issued under the auspices of the German Society of Hematology and Oncology (DGHO), provides an updated, evidence-based framework for the diagnosis and management of this rare, chronic myeloproliferative neoplasm. Developed by a panel of experts (including Germany, Austria and Switzerland) nominated by the DGHO, the guideline reflects a structured and consensus-oriented process in which internationally recognized specialists in hematology critically reviewed the available evidence, revised the written draft, and engaged in multiple rounds of discussion to ensure consistency, clinical relevance, and scientific rigor. This update builds upon the foundation of the previously available ONKOPEDIA guideline (accessible at www.onkopedia.com), but extends and refines the recommendations in light of several important recent developments.

Abstract Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by the driver mutation BRAF V600E. Standard treatment with purine analogs (eg, cladribine) induces long-term remissions, but up to 25% of patients relapse early. Even when targeting BRAF V600E, residual HCL cells frequently persist in the bone marrow (BM). To identify additional biological alterations contributing to HCL persistence, we performed single-cell RNA sequencing of sorted primary HCL cells from long-term vs short-term cladribine responders (ST-R; >10 vs ≤3 years of progression-free survival) at diagnosis and from ST-R at diagnosis vs relapse. We identified a distinct HCL subcluster characterized by increased DUSP1, FOS, and JUND expression that was detected in all patients and persisted or even expanded at relapse. Cancer pathway analysis suggested enhanced tumor microenvironment dependence, as reflected by suppression of the p38 mitogen-activated protein kinase pathway. In the absence of a suitable BRAF V600E-mutated HCL cell line, we validated HAIR-M cells (BRAF D594E) as a bona fide experimental HCL model. The activating BRAF D594E mutation mimics V600E-induced downstream signaling that can be effectively targeted by BRAF inhibitors (BRAFi). HAIR-M coculture with BM stromal cells (BMSC) strongly induced DUSP1 and was accompanied by protection from BRAFi-induced HAIR-M apoptosis. The functional importance of DUSP1 was corroborated by showing that BMSC-induced protection from cell death could be overcome by DUSP1 inhibition. Our results may set the stage for future clinical testing of DUSP1 inhibition to eliminate minimal residual disease and prevent relapse in HCL.

Multiple myeloma (MM) is characterized by the production and secretion of large quantities of immunoglobulins, making this malignancy highly dependent on mechanisms that maintain cellular proteostasis. While significant clinical progress has been made by targeting the degradative branch of proteostasis, much less attention has been given to the biosynthetic branch. In this study, we demonstrated that inhibiting COPII-dependent endoplasmic reticulum (ER) export induces cell death in several MM cell lines and primary patient-derived cells. The induction of cell death was dependent on the secretory status of MM cells. Blocking ER export in secretory MM cells caused the accumulation of misfolded proteins, which activated ER-associated degradation (ERAD). Consequently, we observed an ERAD-dependent increase in the levels of free cytosolic amino acids and a subsequent activation of mTORC1 signaling. Simultaneously, we observed mitochondrial dysfunction. These alterations resulted in a mismatch between the increased energy demand due to mTORC1 activation, and the disrupted energy supply from mitochondrial impairment. This energetic imbalance results in homeostatic collapse and cell death of secretory MM cells. The therapeutic potential of the concept was demonstrated in two in vivo myeloma models. These findings suggest that the ER export machinery could be a promising therapeutic target in multiple myeloma.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition. While few diagnostic scores are established, none exist to predict both clinical course and time-point specific outcome of sHLH patients so far. We present a machine learning (ML)-based tool to predict Initial Disease Severity (IDS; defined as admission to intensive care units (ICU) OR death < 90 days without ICU admission) and mortality across different time points in sHLH patients. 167 adult sHLH patients from six study centers across three European countries were included retrospectively. Clinical and demographic features, course, survival, and laboratory data were assessed. Random forest models were trained with two sets of eight clinical and laboratory features: one to predict IDS, and five to predict mortality at distinct time points (30, 60, 90, 180 or 365 days). After calibration, the models were tested against hold-out test sets containing n = 32 (IDS) or n = 43 (mortality) sHLH patients. Overall, the models demonstrated strong discriminatory ability, overall performance, and accurate prediction of risk. Serum levels of the soluble interleukin-2 receptor (sIL-2R) and albumin (for IDS) or sIL-2R and platelet counts (for mortality prediction) showed the strongest contributions to the models’ predictions. The HLH-Risk-Calculator is an exploratory tool predicting the clinical course of sHLH. External validation is critical to assess its validity, applicability, and robustness for real-world use. To this end, the calculator is available at www.hlh-risk-calculator.com for research use only, and is currently not intended for clinical decision-making.

Measurable residual disease (MRD) can predict relapse in patients with advanced myelodysplastic neoplasms (MDS) or acute myeloid leukemia (AML). We report the long-term efficacy and safety of MRD-guided preemptive azacitidine treatment to prevent relapse in the phase 2 RELAZA2 trial. Patients with MDS or AML after either intensive chemotherapy only or consecutive allogeneic stem cell transplantation were prospectively screened for imminent relapse by molecular MRD assessment. Patients who became MRD positive (MRDpos) during screening received azacitidine for up to 2 years to prevent relapse. The primary endpoint was the proportion of patients alive and relapse-free six months after azacitidine start. Of 357 patients screened, 119 (33.3%) became MRDpos, of whom 95 (79.8%) were eligible for azacitidine treatment. The primary endpoint was met; 60 (63%) patients were relapse-free (95% confidence interval 54-71%, P<0.0001) six months after azacitidine initiation with no new safety signals. Of 60 patients achieving MRD response during the first six cycles of azacitidine, 31 (52%) maintained response without hematological relapse for ≥2 years following azacitidine initiation. The median treatment-free duration following azacitidine discontinuation was 20.8 months; the longest ongoing response was 104 months. After a median follow-up of 6.6 years, 15 initial responders (25%) remained alive and in remission. Among screened patients who remained continuously MRDneg, 60-month overall survival and relapse-free survival were 88% and 79%, respectively. Continuously MRDneg patients display a very favorable prognosis. A majority of MRDpos patients can be effectively treated with azacitidine with potential long-term remission even after termination of azacitidine. Clinicaltrials.gov: NCT01462578.

CBL-B is an intracellular E3 ubiquitin ligase that acts as a T cell checkpoint by raising activation thresholds and limiting effector function. Here, genetic targeting of CBL-B enhances the performance of adoptively transferred T cells and CAR T cells under tumor microenvironment-like stress. In fully immunocompetent mouse models, Cblb deficiency or transient Cblb silencing improves control of MC-38 colon carcinoma and autochthonous mammary tumors, demonstrating that CBL-B restrains anti-tumor immunity. Cblb-deficient T cells show enhanced expansion and effector/effector-memory differentiation during an in vivo mixed lymphocyte reaction, confirming a cell-intrinsic brake function of CBL-B during sustained antigenic challenge. In a syngeneic Panc02-EpCAM model, Cblb-deficient anti-EpCAM CAR T cells show superior tumor control, enhanced infiltration, prolonged survival, and preserved effector function despite chronic antigen exposure and TGF-β. Mechanistically, Cblb targeting maintains granzyme B and IFN-γ production and is associated in vitro with increased GSDME-linked pyroptotic tumor cell death, consistent with features of immunogenic cell death. These findings extend previous CBL-B CAR T work from lymphocyte-deficient to immunocompetent settings and support CBL-B inhibition as a strategy to engineer CAR T cells that resist suppressive tumor microenvironments while promoting a more inflammatory mode of tumor killing.

Myelofibrosis (MF) is a rare, clonal disorder of pluripotent hematopoietic stem and progenitor cells. It is characterized by abnormal proliferation of hematopoiesis, associated with pathologically increased fibrosis in the bone marrow, which is primarily caused by activation of the JAK2 signaling pathway. Myelofibrosis (MF) may occur de novo as primary myelofibrosis (PMF), or secondarily as a consequence of polycythemia vera (PV) or essential thrombocythemia (ET), termed post-PV-MF and post-ET-MF, respectively. The latter two are collectively referred to as secondary myelofibrosis. The most recent updates of the diagnostic criteria by the WHO and ICC were published in 2022. These revisions defined prefibrotic primary myelofibrosis (pre-PMF) as a distinct subentity alongside "classic" overtly fibrotic PMF and secondary myelofibrosis. A hallmark of pre-PMF is an initial isolated thrombocytosis, whereas in overt MF, anemia is frequently present already at diagnosis. Splenomegaly is also more commonly detected at diagnosis in overt fibrotic MF than in pre-PMF. The prognosis of MF is determined by patient age, the presence of constitutional symptoms, as well as hematologic and genetic parameters. Increasingly, cytogenetic and molecular genetic markers play a decisive role. The most common causes of death in MF include transformation to acute myeloid leukemia, infections, and cardiovascular complications. The only potentially curative treatment is allogeneic stem cell transplantation (alloSCT), which is generally indicated in transplant-eligible patients with unfavorable prognosis, that is, those classified as high- or very-high risk according to the MIPSS70+ v2.0. For symptomatic treatment of MF, a variety of therapeutic options are available. In recent years, oral therapy with the JAK1/2 inhibitor ruxolitinib has become the standard of care. Since 2021, the JAK2/FLT3 inhibitor fedratinib has also been approved in the EU (note: in Switzerland, fedratinib will no longer be available as of February 28, 2025, as Swissmedic did not extend its time-limited approval). Since 2024, the JAK1/2 and ACVR1/ALK2 inhibitor momelotinib has been approved for MF treatment in the EU (irrespective of risk category) and in Switzerland (restricted to intermediate- or high-risk disease) for patients with moderate or severe anemia and/or after prior treatment with ruxolitinib. Compared to the other two JAK inhibitors, momelotinib is particularly effective in patients with clinically symptomatic moderate to severe anemia. Results from studies investigating additional JAK inhibitors, combination therapies, and novel agents have also demonstrated significant efficacy and point toward future therapeutic developments, although these approaches are not yet available for routine clinical practice.

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) frequently require red blood cell (RBC) transfusions. Immunomodulation by RBC transfusion is of great interest in the context of alloHSCT, as donor immune cells mediate tumor control, fight pathogens, but also cause graft-versus-host disease (GvHD), a potentially lethal complication of alloHSCT. Data linking RBC transfusion burden with relevant clinical outcome parameters after alloHSCT are scarce. Methods: In this retrospective study, we examined the association between RBC transfusion burden and clinical outcomes in a cohort of 116 patients who underwent alloHSCT at a single transplant center. Therefore, we analyzed the impact of RBC transfusion burden on the following relevant outcomes after alloHSCT: overall survival, leukocyte engraftment, GvHD incidence, and infection rate. Results: Reduced transfusion frequencies, both before (p = 0.003) and after (p = 0.002) alloHSCT, are associated with favorable survival rates 100 days after transplantation. In line, those patients showed an earlier leukocyte engraftment (p < 0.001). However, no significant association was found between the transfusion rate and the incidence of grade II-IV acute GvHD (aGvHD) (p = 0.87). Notably, it was not the frequency of pre-transplant RBC transfusions (p = 0.05), but rather an increased post-transplant transfusion rate (p < 0.001), that was significantly associated with a lower infection rate, particularly with infections within the first 21 days following alloHSCT (p < 0.001 for post-transplant transfusions). Conclusion: In summary, our data support recent evidence that high RBC transfusion burden is associated with poor survival. GvHD incidence was not linked to RBC transfusion, but we were able to detect a negative association with infectious complications. Larger, multi-center trials are needed to confirm our findings, accompanied by molecular analysis of RBC-immune cell interactions.

Extramedullary acute myeloid leukemia (EML) is a rare manifestation of acute myeloid leukemia (AML), where myeloid blasts invade extrahematopoietic tissues. Recent data highlight a negative prognostic impact of EML. The knowledge about the molecular pathogenesis behind EML is insufficient and mainly derived from the analysis of corresponding bone marrow (BM) manifestations. We aimed to shed more light on the molecular pathogenesis of EML and performed next-generation sequencing (NGS) of 49 myeloid neoplasm-associated genes in paraffin-embedded EML biopsies of 76 patients. Our analyses validated the high frequency of mutations in NPM1 (26%), DNMT3A (21%), TET2 (19%), and FLT3 (16%). In addition, 43% of patients exhibited one or more mutations in RAS or RAS-modifying genes (RASmut; NRAS, KRAS, PTPN11, CBL, NF1). The frequency of RASmutwas significantly higher in EML biopsies as compared to BM specimens from four unselected AML cohorts comprising more than 1400 patients (cohort Graz, 81/278 [29%], P=0.015; cohort TCGA-LAML, 34/200 [17%], P<0.001; cohort Beat-AML, 217/785 [28%], P=0.023; cohort TARGET-AML, 40/150 [27%], P=0.035). Paired NGS results of EML biopsies and affected BM of the corresponding patients were available in 22 cases. Of these, four patients developed a RASmut in the EML specimen that was not present in the BM. Furthermore, the normalized variant allele frequencies (VAF) of RASmut in the EML specimen were significantly higher compared to those in the corresponding AML BM (70% vs 40%, P=0.002). To clarify the functional role of RASmut in the tissue infiltration of myeloid blasts and EML formation. Therefore, we introduced the NRASG12D mutation in the RAS-wildtype (WT) myeloid leukemia cell line K562 by employing the CRISPR/Cas9 knock-in strategy to establish an isogenic cell line model. This mutation was chosen as it was the most frequent alteration detected in the primary EML specimens. In-vitro, K562-NRASG12D showed higher rates of migration (P=0.034) and invasion (P=0.035) compared to K562-NRASWTcells, with no changes in proliferation (P=0.287). To exclude cell line specific effects, and ensure that the findings are also applicable to other RASmut (beyond NRASG12D), these analyses were validated in another cell line model (HEL-NRASG12D vs HEL-NRASWT; P=0.02 for migration and P=0.005 for invasion) and murine hematopoietic progenitors carrying KrasG12D (Mx1-Cre/KrasG12D vs Mx1-Cre/KrasWt; P=0.01 for migration and P=0.004 for invasion). We then validated the effects of RASmut on EML formation and invasion in ex-ovo chorioallantoic membrane (CAM) assays in chicken embryos. In agreement with the in-vitro assays, K562-NRASG12D invaded significantly better and formed larger tumors in the CAM than K562-NRASWT(P=0.0246). We then aimed to validate these data in-vivo and injected the K562 cells subcutaneously into immunocompromised NRG nude mice. This way of administration was preferred over the intravenous route as we aimed to transfer the cells into an extramedullary environment. Again, K562-NRASG12D formed significantly bigger tumors than K562-NRASWT(P=0.011). To delineate the mechanisms behind RASmut-driven leukemic tissue infiltration, we performed RNA sequencing of the subcutaneous NRASG12D and NRASWT tumors. This analysis revealed 244 differentially expressed genes with the majority (n=185) showing decreased expression in NRASG12D tumors. As we were mainly interested in identifying candidate genes amenable to direct therapeutic targeting, we focused on the 59 genes with increased expression in the NRASG12D-mutated tumors. Candidate selection via comparison with the Beat-AML cohort and literature review, and validation by qPCR and Immunoblot revealed the junctional adhesion molecule-like protein (JAML) as the most promising target. Indeed, the causative role of JAML expression could be corroborated by repeating the migration assays, where siRNA-mediated JAML knockdown in K562-NRASG12D significantly decreased the migration potential of these cells (P=0.007).Taken together, we delineate the molecular landscape of EML and show that RASmut are associated with the development of this AML subform. We further show that RASmut are functionally involved in the tissue infiltration of leukemic blasts and EML formation. Finally, we show that upregulation of JAML is a central step in RASmut-mediated EML formation and represents an interesting therapeutic target for RASmut EML manifestations.

Chronic inflammation has been recognized as a key contributor to cancer initiation, progression, and treatment response across various malignancies. In this short review we summarize the key takeaways from ASCO 2025 with regard to studies presented on chronic inflammation and cancer. Emerging evidence suggests that systemic inflammation can be modulated by lifestyle-based interventions such as diet or physical activity. Systemic inflammation may also contribute to complex symptoms such as cancer-related fatigue or depression, impairing quality of life. Markers of systemic inflammation such as the neutrophil-to-lymphocyte ratio can be used as prognostic markers and highlight the role of myeloid-driven inflammation in cancer. In line with this, clonal hematopoiesis—an aging-associated condition of clonal myeloid immune cell expansion—is commonly identified infiltrating solid cancers, shaping the immune landscape of the tumor microenvironment and thereby modulating cancer behavior and therapy effectivity.