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At least 19 recordsLinked to original sources
PubMed2025

Evolution of primate T-cell leukemia virus type 1 accessory genes and functional divergence of its antisense proteins.

Human T-cell leukemia virus type 1 (HTLV-1) is derived from simian T-cell leukemia virus type 1 (STLV-1), and together they form a broader category known as primate T-cell leukemia virus type 1 (PTLV-1). PTLV-1 encodes multiple proteins from overlapping open reading frames (ORFs) in the pX region. This study aims to characterize the conservation of these proteins in different PTLV-1 subtypes and their role in pathogenesis. For the first time, we report the full-length proviral sequence of an STLV-1 strain isolated from chimpanzee and African green monkey. Phylogenetic analysis reveals high conservation of the accessory proteins p12, p30, and p13 in the HTLV-1a subtype. Conversely, some African PTLV-1 subtypes exhibit loss of ORFs for p12 or p13. For Asian subtypes, simian strains often lack p12, p13, or p30 proteins, whereas human strains retain the ORFs of p30 and p13 but not p12. To assess the infectivity of a simian strain of PTLV-1 lacking ORFs for p12, p13, and p30, we constructed a molecular clone from a naturally infected Japanese macaque (Mfu: Macaca fuscata) and compared it with HTLV-1a. Using a reporter assay and ELISA, we found similar infectivity to Jurkat T cells; however, STLV-1 Mfu exhibited impaired infectivity in the monocytic cell line THP-1. Additionally, despite the conservation of the HTLV-1/STLV-1 bZIP factor (HBZ/SBZ) ORFs, HBZ/SBZ proteins derived from HTLV-1a and African PTLV-1 subtypes induce significantly higher activation of the TGF-β/Smad signaling pathway than those from Asian subtypes. Collectively, our findings suggest that the acquisition of the accessory proteins by PTLV-1 subtypes potentially confers an advantageous adaptation of PTLV-1 during infection in apes, including humans. Moreover, among PTLV-1 strains, HBZ/SBZ had varying degrees of activity on the TGF-β/Smad pathway; this fact underscores the complex interplay between viral proteins and host signaling pathways, possibly influencing the viral pathogenicity in different species.

Animals↗
PubMed2025

Role of the CTCF binding site in Human T-Cell Leukemia Virus-1 pathogenesis.

During HTLV-1 infection, the virus integrates into the host cell genome as a provirus with a single CCCTC binding protein (CTCF) binding site (vCTCF-BS), which acts as an insulator between transcriptionally active and inactive regions. Previous studies have shown that the vCTCF-BS is important for maintenance of chromatin structure, regulation of viral expression, and DNA and histone methylation. Here, we show that the vCTCF-BS also regulates viral infection and pathogenesis in vivo in a humanized (Hu) mouse model of adult T-cell leukemia/lymphoma. Three cell lines were used to initiate infection of the Hu-mice, i) HTLV-1-WT which carries an intact HTLV-1 provirus genome, ii) HTLV-1-CTCF, which contains a provirus with a mutated vCTCF-BS which abolishes CTCF binding, and a stop codon immediately upstream of the mutated vCTCF-BS which deletes the last 23 amino acids of the p12 gene, and iii) HTLV-1-p12stop that contains the intact vCTCF-BS, but retains the same stop codon in p12 as in the HTLV-1-CTCF cell line. Hu-mice were infected with mitomycin-treated or irradiated HTLV-1 producing cell lines. There was a delay in pathogenicity when Hu-mice were infected with the HTLV-1-CTCF virus compared to mice infected with either HTLV-1-p12 stop or HTLV-1-WT virus. Proviral load (PVL), spleen weights, and CD4 T cell counts were significantly lower in HTLV-1-CTCF infected mice compared to HTLV-1-p12stop infected mice. Furthermore, we found a direct correlation between the PVL in peripheral blood and death of HTLV-1-CTCF infected mice. In cell lines, we found that the vCTCF-BS regulates Tax expression in a time-dependent manner. The scRNAseq analysis of splenocytes from infected mice suggests that the vCTCF-BS plays an important role in activation and expansion of T lymphocytes in vivo. Overall, these findings indicate that the vCTCF-BS regulates Tax expression, proviral load, and HTLV pathogenicity in vivo.

Human T-lymphotropic virus 1↗
PubMed2025

The common murine retroviral integration site activating Hhex marks a distal regulatory enhancer co-opted in human early T-cell precursor leukemia.

The Hhex gene encodes a transcription factor that is important for both embryonic and post-natal development, especially of hematopoietic tissues. Hhex is one of the most common sites of retroviral integration in mouse models. We found the most common integrations in AKXD (recombinant inbred strains) T-ALLs occur 57-61kb 3' of Hhex and activate Hhex gene expression. The genomic region of murine leukemia virus (MLV) integrations has features of a developmental stage-specific cis regulatory element (CRE), as evidenced by ATAC-seq in murine progenitor cells and high H3K27 acetylation at the syntenic CRE in human hematopoietic cell lines. With ChIP-exonuclease, we describe occupancy of LIM domain binding protein 1 (LDB1), the constitutive partner of the LIM Only-2 (LMO2), GATA1, and TAL1 transcription factors at GATA sites and at a composite GATA-E box within the CRE. With virtual 4C analysis, we observed looping between this +65kb CRE and the proximal intron one enhancer of HHEX in primary human ETP-ALLs and in normal progenitor cells. Our results show that retroviral integrations at intergenic sites can mark and take advantage of CREs. Specifically, in the case of HHEX activation, this newly described +65kb CRE is co-opted in the pathogenesis of ETP-ALL by the LMO2/LDB1 complex.

Humans↗
PubMed2026

HMGB1 as a convergent host factor in virus-induced carcinogenesis.

High-mobility group box 1 (HMGB1) is a chromatin-associated protein and a prototypical damage-associated molecular pattern whose dual intracellular and extracellular functions are increasingly implicated in cancer progression. Because viral proteins can harness HMGB1 to facilitate their own replication and remodel the microenvironment of transformed cells, human oncogenic viruses provide an instructive model for examining this duality. In this conceptual review, we organized the available evidence around two functional nodes. At the first node, intracellular HMGB1 supports viral replication, acting on viral chromatin in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus, and on structured viral RNA in hepatitis C virus. At the second node, viral infection or specific viral oncoproteins induce HMGB1 secretion, which promotes infected-cell survival and remodels the tumor microenvironment, as reported for KSHV, hepatitis B virus, and human T-cell leukemia virus type 1. Human papillomavirus engage a receptor-level variant of this node through the HMGB1-TLR4 axis. Only KSHV currently supports both nodes in matched experimental systems. Therefore, we present a sequential two-node arrangement as a hypothesis, instead of an established property of oncogenic viruses. We further considered how viruses reverse the tumor-suppressive, genome-stabilizing functions of nuclear HMGB1, with conserved and divergent strategies apparent across viral families; why the absence of HMGB1 data for Merkel cell polyomavirus is a tractable and informative gap; and which HMGB1- and RAGE-directed agents are realistically positioned for evaluation in virus-associated cancers.

Damage-associated molecular pattern↗
PubMed2026

Conserved host-exclusive oligonucleotide motifs enriched in pathogenic genes of human oncogenic viruses.

Comparative viral genomics can reveal sequence-level constraints influencing virus-host interactions. Relative minimal absent words (rMAWs) are short oligonucleotide motifs present in viral genomes but completely absent from the host, potentially reflecting selective pressures related to host adaptation and immune evasion. Using the EAGLE algorithm and the GRCh38 human reference genome, we systematically screened for prevalent rMAWs (prMAWs) across six major human oncogenic viruses: Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), human T-cell leukemia virus type 1 (HTLV-1), and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). highly conserved 11- and 12-bp prMAWs were identified in EBV, HBV, HTLV-1, and HHV-8/KSHV, with sequence prevalences ranging from 91.5% to 97.9%. Conversely, no short prMAWs were detected in HCV or HPV, likely reflecting differences in genome architecture, mutation rates, and long-term host adaptation to the human host. Importantly, the identified host-exclusive motifs exhibited non-random genomic distribution and were preferentially embedded within viral genes central to replication, persistence, immune modulation, and oncogenesis, including EBNA-1 (EBV), HBx (HBV), Tax-associated regions (HTLV-1), and lytic replication genes of HHV-8/KSHV. Notably, all detected prMAWs were enriched in GC nucleotides and exhibited marked CpG over-representation, suggesting sequence constraints associated with epigenetic regulation and viral persistence. Collectively, these highly conserved, host-exclusive signatures offer promising, candidates for sequence-directed approaches in the diagnosis, monitoring, and investigation of virus-associated cancers.

Humans↗
PubMed2026

FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.

UNLABELLED: FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematologic malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, whereas FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6-deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T-cell effector function, and decreased expression of T-cell exhaustion markers compared with Cmtm6-proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T-cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, whereas FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 were validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape. SIGNIFICANCE: Activation of the CMTM6/PD-L1 axis in FLT3-ITD-driven acute myeloid leukemia mediates immunosuppression, providing the basis for potential inhibition of this pathway to harness antitumor immunity.

Animals↗
PubMed2026

The machine-learning classifier ALLCatchR2 identifies 20 T-ALL subtypes across cohorts and age groups.

T-cell acute lymphoblastic leukemia (T-ALL) comprises molecularly diverse subtypes, but robust cross-cohort validations and operational gene-expression definitions are lacking. To establish a gene-expression-anchored framework for T-ALL subtyping, we aggregated 2314 transcriptomes (15 cohorts, age: 0.8-90.8 years). An extended unsupervised approach defined 17 main clusters and 3 subclusters in samples with high blast fractions. Supervised analyses added an overarching immature T-ALL (early T cell precursor [ETP]-like) definition and resolved the LMO2 &#x3b3;&#x3b4;-like subtype. All clusters contained samples from at least two cohorts. Characteristic genomic driver enrichments were consistent across cohorts, while gene-expression clusters did not correspond exclusively to single driver events but also reflected developmental origins. A machine-learning classifier based on ALLCatchR, our B-cell acute lymphoblastic leukemia (B-ALL) classifier, identified these 20 transcriptomic subtypes and the immature T-ALL (ETP-like) signature with 0.995-1.0 accuracy in a validation set (n&#x2009;=&#x2009;203). Testing the classifier on a second hold-out data set (n&#x2009;=&#x2009;265 samples) showed that 92.7% of predictions matched with corresponding driver alterations. Across all samples, 83.2% of cases received high-confidence predictions, 7.3% candidate predictions, and 9.5% remained unclassified, largely because of low blast fractions. We identified a novel gene-expression cluster markedly enriched (P&#x2009;<&#x2009;0.001) for clonal hematopoiesis mutations (IDH2 R140Q, DNMT3A) and a stem-/progenitor cell-like gene expression. This novel clonal hematopoiesis-related T-ALL subtype was observed in six cohorts and accounted for 8.9% of adults and 39.5% of patients aged >50 years. We extended&#xa0;ALLCatchR into ALLCatchR2, a free R package that now enables B-/T-lineage separation, gene-expression subtyping, blast estimation, and developmental annotation to harmonize T-ALL classification across studies and clinical contexts.

Journal Article↗
PubMed2026

Blinatumomab for Replacing Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

BACKGROUND: Blinatumomab, a bispecific T-cell engager targeting the CD19 antigen on B cells, may offer an option to safely replace cycles of traditional chemotherapy in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL). METHODS: We randomly assigned, in a 1:1 ratio, children with high-risk B-cell ALL to receive two cycles of blinatumomab (blinatumomab group) or two cycles of chemotherapy (control group) after consolidation. The primary end point was event-free survival as evaluated in a time-to-event analysis; the duration of event-free survival was defined as the time from randomization to the first event among resistance to protocol treatment, relapse, second cancer, or death from any cause. Our primary objective was to evaluate whether the 4-year event-free survival would be 10 percentage points higher in the blinatumomab group than in the control group. RESULTS: Overall, 709 of 768 eligible patients (92.3%) underwent randomization; 358 were assigned to the blinatumomab group and 351 to the control group. A planned interim analysis at a median follow-up of 2.9 years showed an estimated 4-year event-free survival of 83.0% (95% confidence interval [CI], 77.4 to 87.4) in the blinatumomab group and 70.3% (95% CI, 63.8 to 75.9) in the control group (P&#x2009;=&#x2009;0.0002 in an intention-to-treat analysis). The estimated hazard ratio for a primary end-point event (blinatumomab vs. control) was 0.51 (95% CI, 0.35 to 0.73) as assessed with a Cox model. Infection related to the trial treatment occurred in 23.9% of patients in the blinatumomab group and in 69.4% of those in the control group (P<0.001). Life-threatening adverse events occurred in 2 patients (0.5%) in the blinatumomab group, including one (in 0.3%) that was fatal, and in 16 patients (4.7%) in the control group. Neurotoxic events were reported in 12.0% and 3.2%, respectively (P<0.001). Cytokine release syndrome of grade 2 or higher occurred in 1.1% of patients in the blinatumomab group. CONCLUSIONS: In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival at 4 years. (Funded by Deutsche Krebshilfe and others; AIEOP-BFM ALL 2017 EudraCT number, 2016-001935-12; EU Clinical Trials number, 2023-509856-32-00; and ClinicalTrials.gov number, NCT03643276.).

Adolescent↗
PubMed2025

A viral clonality evenness score to predict progression to adult T-cell leukaemia in asymptomatic carriers of human T-lymphotropic virus type 1 in Japan: a retrospective longitudinal cohort study.

BACKGROUND: Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that occurs in approximately 2-7% of individuals with human T-lymphotropic virus type 1 (HTLV-1), after decades of asymptomatic infection. To address the urgent need for predictive biomarkers to identify asymptomatic carriers of HTLV-1 at high risk of progression to ATL, we aimed to evaluate viral clonality sequencing as a potential tool for risk stratification. METHODS: This retrospective longitudinal cohort study involved HTLV-1 carriers enrolled in the Joint Study on Predisposing Factors of ATL Development, a nationwide cohort study initiated in Japan in 2002. Participants were selected from this cohort on the basis of their baseline proviral load at the time of enrolment as an asymptomatic carrier, length of follow-up, and clinical outcome. The cohort was subdivided into three subgroups: the first comprising HTLV-1 carriers who developed ATL, the second comprising carriers with high proviral load (&#x2265;4%) who did not progress to ATL, and the third comprising carriers with low proviral load (<4%) who did not progress to ATL. DNA extracted from peripheral blood mononuclear cells collected at enrolment and at least one follow-up visit was analysed by HTLV-1 clonality sequencing and the proviral load was quantified. We calculated a viral clonality evenness (VCE) score, based on the Shannon Evenness Index, to quantify the uniformity of the clonal distribution of samples, for which 0 represents a perfectly monoclonal architecture and 1 indicates a completely polyclonal landscape. We then estimated the performance of proviral load thresholds and VCE scoring to classify the risk of progression to ATL using the area under the receiver operating characteristic curve (AUC), the accuracy, and Matthews correlation coefficient. VCEs were compared between participant subgroups with the Wilcoxon rank sum test. FINDINGS: 56 participants followed up by JSPFAD between Feb 6, 2003, and July 19, 2022, were included in this study: 17 who progressed to ATL (mean follow-up 8&#xb7;3 years [SD 4&#xb7;0]), 18 who had a high proviral load and did not progress to ATL (9&#xb7;7 years [3&#xb7;4]), and 21 who had a low proviral load and did not progress to ATL (7&#xb7;5 years [3&#xb7;0]). Clonality sequencing of samples from 39 participants who did not progress to ATL revealed hundreds to thousands of HTLV-1 integration sites at both timepoints, corresponding to multiple clones of low and uniform abundance, and these participants had high VCE scores (&#x2265;0&#xb7;694) at baseline. By contrast, most participants (14 of 17) who progressed to ATL had a single predominant clone or two to four predominant clones at both timepoints, and lower VCE scores (<0&#xb7;694) at baseline than those who did not progress (p<0&#xb7;0001). AUCs were very similar for proviral load thresholds (91 [95% CI 80-98]) and VCE scoring (91 [78-100]), although when using methods that give equal weight to every individual, VCE scoring outperformed proviral load thresholds in predicting progression to ATL (accuracy: proviral load 0&#xb7;76 [95% CI 0&#xb7;76-0&#xb7;77], VCE scoring 1&#xb7;00 [0&#xb7;99-1&#xb7;00]; Matthews correlation coefficient: proviral load 0&#xb7;23 [95% CI 0&#xb7;19-0&#xb7;24], VCE scoring 0&#xb7;91 [0&#xb7;80-1&#xb7;00]). Prediction based on VCE scoring indicated no false positives, compared with 20% when using proviral load, although VCE scoring yields a greater number of false negatives (0&#xb7;3% vs 0&#xb7;1%). INTERPRETATION: The implementation of VCE scoring in clinical practice could inform early pre-emptive therapeutic interventions, exclusively targeting individuals with HTLV-1 at high risk and aiming to prevent progression to aggressive, treatment-refractory disease. Further validation, including independent confirmation of the performance of VCE scoring in multiple populations and the characterisation of its temporal dynamics, will be crucial to determine its clinical utility and potential integration into care pathways. FUNDING: Association Jules Bordet, FNRS-T&#xe9;l&#xe9;vie, FCC, WALInnov, FLF, JSPS-KAKENHI, and CoBiA.

Humans↗
PubMed2026

[Development of universal off-the-shelf T cell therapies derived from ES/iPS cells for leukemia and COVID-19].

Cancer immunotherapy using patient-derived T cells genetically modified in vitro has been demonstrated to be effective. However, issues such as cost, time, and unstable quality must be resolved. To overcome these barriers, we developed the TCR-PS cell method, in which a specific TCR gene is introduced into pluripotent stem cells (PS cells), such as ES cells or iPS cells, and T cells are generated from those PS cells. We are currently preparing for a clinical trial in acute myeloid leukemia, targeting the WT1 antigen, with iPS cells provided by the CiRA Foundation as the starting material. In parallel, we are also investigating this approach for viral infections and preparing for clinical trials in COVID-19, with HLA-deficient ES cells as the starting material. This method should enable stockpiling of T cell therapies against known viruses such as SARS or avian influenza. Even for outbreaks caused by unknown viruses, it should be possible to produce T cell therapies within 100 days after the virus genome is defined.

Humans↗
PubMed2026

Hemophagocytic Lymphohistiocytosis and Fibroblast Growth Factor 23 (FGF23)-Induced Hypophosphatemia.

Hypophosphatemia is a frequent complication of chimeric antigen receptor T-cell therapy. In this setting, hypophosphatemia has been previously associated with cytokine release syndrome. The mechanisms underlying this electrolyte derangement are not fully understood. Extracellular phosphate consumption by chimeric antigen receptor T cells was demonstrated in vitro, but inflammation is also thought to play a contributing role. We present a case of severe, refractory hypophosphatemia with renal phosphate wasting triggered by hemophagocytic lymphohistiocytosis in acute lymphoblastic leukemia. The diagnosis of phosphate wasting was made at the onset of leukemia and a clinical exacerbation occurred after chimeric antigen receptor T-cell therapy. Diagnostic workup revealed very high fibroblast growth factor 23 (FGF23) levels in the absence of recognized acquired or genetic causes of impaired FGF23 cleavage. This case suggests that inflammation associated with hemophagocytic lymphohistiocytosis may induce FGF23 as a potential mechanism for hypophosphatemia. In this context, we recommend evaluation of renal phosphate wasting and subsequently FGF23 in patients with persistent hypophosphatemia despite standard supplementation.

Humans↗
PubMed2026

Pre-treatment T cell features and immune-milieu characteristics shape treatment-induced exhaustion and resistance to Blinatumomab in B-cell acute lymphoblastic leukemia.

BACKGROUND: Blinatumomab (Blina), a CD19&#xd7;CD3 bispecific T cell engager, is approved for the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), yet resistance remains a major challenge and the mechanisms driving treatment failure remain poorly understood. METHODS: To define the immunological determinants of resistance, we performed longitudinal profiling of peripheral blood T cells and the immune milieu of 34 patients receiving Blina using flow cytometry (n=19), single-cell CITE-seq (n=13), ex vivo Blina-induced cytotoxicity (n=26) and serum proteomics (n=17). RESULTS: At baseline, Responders (R) were enriched for CD8+ effector memory T cells (TEM) expressing higher levels of cytotoxic genes and their transcriptional regulator ZNF683. Conversely, CD8+ TEM from Non-Responders (NR) displayed transcriptional features of activation without proportionate cytotoxic commitment. Over the course of the first treatment cycle, NR exhibited a progressive expansion of TIM3+CD8+ T cells that correlated with a rapid loss of ex vivo cytotoxic function. Linking baseline state to post-treatment T-cell exhaustion, the magnitude of TIM3+CD8+ expansion correlated inversely with baseline ZNF683 expression in CD8+TEM. Beyond T-cell-intrinsic features, NR harbored an immunosuppressive milieu characterized by higher circulating levels of M2-polarizing factors (CSF-1, HGF) and the TIM-3 ligand Galectin-9, which correlated positively with the magnitude of TIM3+CD8+ T-cell expansion. CONCLUSIONS: These findings indicate that post-Blina CD8+ T-cell exhaustion is associated with resistance and it is shaped by both reduced ZNF683-dependent cytotoxic programming in CD8+ TEM and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8+ TEM and for combinatorial strategies targeting the suppressive microenvironment.

Humans↗
PubMed2014

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.

Animals↗
PubMed2026

The 21st International ``Ponte di Legno'' Childhood Acute Lymphoblastic Leukemia Workshop Report: Progress and Emerging Opportunities.

The 21st Ponte di Legno Working Group meeting convened in Orlando, USA, on December 4-5, 2025, bringing together leading childhood acute lymphoblastic leukemia (ALL) investigators from major global consortia. In response to the transformative advances in childhood ALL treatment, particularly the integration of immunotherapy into frontline therapy, the group revisited and updated its mission statement. The revised mission emphasizes collaborative studies on rare leukemia subsets, harmonized toxicity reporting, particularly for immunotherapy-related toxicities, and unrestricted worldwide collaboration. In addition, sharing data and strategies for integrating novel agents will be integral to optimizing future trial design. Key scientific topics included rare genetic subgroups, T-cell ALL genomics, treatment-related toxicity benchmarking, and central nervous system (CNS) disease management challenges. A major focus was immunotherapy integration into frontline therapy, particularly blinatumomab as an emerging standard of care and inotuzumab ozogamicin as an investigational agent, and their potential to enable chemotherapy de-escalation. Additional discussions addressed immunotherapy-specific toxicities. The integration of immunotherapy into frontline ALL therapy represents a paradigm shift with potential to improve outcomes while reducing treatment burden. However, careful attention to CNS disease control, emerging toxicities, and preservation of the remarkable achievements in childhood ALL therapy remains essential as the field advances.

Blinatumomab↗
PubMed1978

Rosette formation of human null lymphocytes with Rhesus monkey erythrocytes.

Human null lymphocytes which lack B- and T-lymphocyte markers were found to form spontaneous rosettes with uncoated Rhesus monkey erythrocytes. Rosette-forming null lymphocytes were determined in null lymphocyte-enriched preparations of healthy persons and of patients with lymphoproliferative diseases. Quantitative determinations of these rosette-forming lymphocytes and other cells bearing B- or T-cell markers showed that some, and not all, of the null lymphocytes possess this rosette-forming capacity. The possibility of these null lymphocytes being related to T lymphocytes, but at a different cellular stage, is discussed.

Animals↗
PubMed2026

CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles.

UNLABELLED: Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target lineage-specific surface antigens. However, CAR T cells show limited efficacy against myeloid neoplasms and solid tumors due to challenges in identifying suitable surface targets. In this study, we present a CAR targeting the intracellular WT1 oncoprotein, cross-presented by surface HLA class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1- and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This approach broadens CAR-targetable antigens beyond traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. SIGNIFICANCE: Leveraging the promiscuous binding of HLA-II-peptide complexes, we developed a CAR T-cell approach targeting an intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study establishes a framework for CAR therapies against intracellular antigens, extending potential CAR T-cell applications to new cancer types and patient populations.

Humans↗
PubMed2026

GATA2 deficiency: enhancer deregulation, immune surveillance failure, and clonal evolution.

Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.

Humans↗