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• Clinical and Molecular Investigation of Familial CEBPA-mutated Acute Myeloid Leukaemia

  Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are clonal diseases arising from the sequential acquisition of genetic aberrations in haematopoietic stem cells. Whilst the aetiology is predominantly sporadic, rare reports describe the autosomal dominant inheritance of MDS and AML (familial MDS/AML), often presenting in younger patients (<40 years of age) with a germline mutation in one of three haematopoietic transcription factors: RUNX1, CEBPA and GATA2. The clinical recognition of familial disease can be challenging due to wide variations in phenotype, latency and transmission, complicated further by the patients’ awareness and reporting of affected relatives. Distinct clinical manifestations have however been reported for each genetic subtype and whilst RUNX1 and GATA2 mutations can harbour prolonged dysplastic or cytopenic phases, germline CEBPA mutations universally present with AML de novo. Our group were the first to describe germline CEBPA mutations in 3 related individuals, all of whom developed AML between 10-30 years of age. The initial pedigree together with those described in the intervening period, were predominantly isolated case reports with limited follow up, hence long term outcomes for this group of patients remain poorly defined. This contrasts with CEBPA mutations occurring in 10-15% of sporadic AML with normal karytoype (NK-AML), where double mutations (CEBPAdm, found in approximately 50% of all CEBPA-AML) are considered a unique molecular entity, associated with favourable clinical outcomes. In sporadic and familial CEBPAdm AML, N’ terminal mutations enforce translation of the shorter P30-kDa isoform and are typically accompanied by C’ terminal insertions or deletions (disrupting the DNA-binding and/or Leucine zipper domains). Definition of the full molecular landscape awaits extensive whole exome sequencing, although GATA2 mutations (targeting the Zinc Finger 1, ZF1, domain) have been reported in 20-40% of sporadic CEBPAdm AML and recent targeted resequencing analysis revealed a further association with WT1 mutations. With minimal clinical and molecular information available for familial CEBPA-AML, we are often consulted regarding the management of this unique patient population. To address this need, we have investigated a multi-centre cohort of families with germline CEBPA mutations, providing extended clinical follow up, whole exome profiling of secondary mutations and molecular analysis of relapsed disease.

  Study EGAS00001000949

• Sequence data to study genomic CNVs that drive apoptotic resistance and relapses on immune checkpoint inhibitors

  This project investigates the genomic mechanisms underlying acquired resistance to immune checkpoint inhibitors (ICIs) across tumor types, addressing the critical clinical problem of treatment relapses where the molecular basis remains poorly understood. Through integrative genomic analyses of longitudinal clinical melanomas, functional CRISPR-Cas9 screens, and human and murine melanoma models, the study demonstrates that copy-number variant (CNV)-driven subclonal evolution is a primary driver of clinical relapses. The research identifies resistance-driver genes targeted by CNVs, including pro-apoptotic gene deletions and anti-apoptotic gene amplifications, which collectively downregulate apoptotic priming in resistant cells. The findings establish that modulating the apoptotic threshold can prevent or reverse ICI resistance, positioning CNV evolution as a key driver of acquired resistance and identifying apoptotic regulation as a therapeutic target to combat resistance evolution.

  Study EGAS50000001055

• Targeting AXL Kinase Uniquely Sensitizes Therapy-Insensitive Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia

  The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in leukemic stem cells. We developed a potent, selective AXL inhibitor that has excellent pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in vivo. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.

  Study EGAS00001004663

• Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing

  Intratumoral heterogeneity (ITH) has been linked to decreased efficacy of clinical treatments. However, although genomic ITH has been characterized in genetic, transcriptomic and epigenetic alterations are hallmarks of esophageal squamous cell carcinoma (ESCC), the extent to which these are heterogeneous in ESCC has not been explored in a unified framework. Further, the extent to which tumor-infiltrated T lymphocytes (TILs) are directed against cancer cells, but how the immune infiltration acts as a selective force to shape the clonal evolution of ESCC is unclear. In this study, we perform multi-omic sequencing on 186 samples from 36 primary ESCC patients. Through multi-omics analyses, it is discovered that genomic, epigenomic, and transcriptomic ITH are underpinned by ongoing chromosomal instability. Based on the RNA-seq data, we observe diverse levels of immune infiltrate across different tumor sites from the same tumor. We reveal genetic mechanisms of neoantigen evasion under distinct selection pressure from the diverse immune microenvironment. Overall, our work offers an avenue of dissecting the complex contribution of the multi-omics level to the ITH in ESCC and thereby enhances the development of clinical therapy.

  Dataset EGAD00001009482

• Butyrate producers as potential next-generation probiotics: safety assessment of the administration of Butyricicoccus pullicaecorum to healthy volunteers

  Advances in gut microbiota research have triggered interest in developing colon butyrate producers as niche-specific next-generation probiotics, targeted at increasing colon butyrate production and countering disease-associated microbiota alterations. Crucial steps in the development of next-generation probiotics are the design of formulations with a reasonable shelf life as well as the safety demonstration of an intervention in healthy volunteers. One such potential next-generation butyrate-producing probiotic is Butyricicoccus pullicaecorum 25-3T, with demonstrated safety in in vitro as well as in animal models. Here, we examined the strain's safety, tolerability, and impact on microbiota composition and metabolic activity in healthy volunteers in a randomized, double blind, placebo-controlled, crossover study in 30 healthy volunteers. Study design consisted of two four-week intervention periods (108 CFU B. pullicaecorum [treatment] or maltodextrin [placebo] per day) with a three-week washout in between. We assessed adverse events, blood parameters (primary endpoints), and fecal microbiota composition and metabolite profiles (secondary endpoints).The number of reported adverse events during the B. pullicaecorum treatment was similar to placebo intervention, as were observed changes in blood chemistry parameters, bowel habits, and fecal calprotectin concentrations. Administration of the strain did not induce any disruptive effect in microbiota composition or metabolic activity. In this first human intervention trial with a butyrate-producing Clostridium cluster IV isolate, we demonstrated B. pullicaecorum 25-3T administration to be both safe and well tolerated by healthy participants. This safety study paves the way for the further development of the strain as a next-generation probiotic.

  Study EGAS00001003276

• Whole Genome Sequencing of Neuroblastoma

  Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2-5. Here we present a whole genome sequence analysis of 87 neuroblastoma of all stages. Only few recurrent amino-acid changing mutations were found. In contrast, analysis of structural defects identified in 18% of high stage neuroblastoma a local shredding of chromosomes, known as chromothripsis6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7-9. In addition, ATRX, TIAM1 and a series of regulators of the Rac Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumors with defects in these genes were aggressive high stage neuroblastoma, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromotripsis and neuritogenesis gene alterations, which frequently occur in high risk tumors.

  Study EGAS00001000222

• Transcriptomes of human CD4+ T lymphocytes - Metabolic project

  Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, while early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T cell proliferation, but not T cell activation. Conditions that inhibited T cell activation were associated with the downregulation of 2′,5′-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress and/or the function of T cells in these conditions will improve the efficacy of T cell-based therapies.

  Study EGAS00001005565

• Single-nucleus transcriptomic profiling of aging Down Syndrome brains

  Down syndrome (DS) – trisomy of human chromosome 21 (HSA21) – is characterized by lifelong cognitive impairments and development of neuropathological hallmarks of Alzheimer’s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA-sequencing (snRNA-seq) employing both short (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1. Long-read sequencing detected vast RNA isoform diversity within and amongst specific cell types including numerous novel sequences that differed between DS and normal brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions (IEJs), including APP that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as novel features of the aging DS brain.

  Study EGAS00001005691

• Monitoring of leukemia clones in B-cell acute lymphoblastic leukemia at diagnosis and during treatment by single-cell DNA amplicon sequencing

  Acute lymphoblastic leukemia (ALL) is characterized by the presence of chromosomal changes, including numerical changes, translocations and deletions, which are often associated with additional single nucleotide mutations. In this study we used single-cell targeted DNA sequencing to determine the clonal heterogeneity of B-cell ALL at diagnosis and during chemotherapy treatment. With a customly designed DNA amplicon library targeting the most common mutations (in 110 genes) present in ALL, we analyzed bone marrow samples and/or blood samples from 12 B-ALL cases at diagnosis. For 4 cases where we detected multiple mutational clones at diagnosis, we also studied blood samples during the first weeks of chemotherapy treatment. This study shows that B-ALL cases with either a ETV6-RUNX1 or a BCR-ABL1 fusion have a low mutational burden, while cases with PAX5 alterations or hyperdyploidy have multiple clones at diagnosis, often with mutations in the JAK-STAT signaling pathway and the RAS signaling pathway. As expected, it can be observed that these clones disappear during treatment of the leukemia with almost no mutated cells left after two weeks of treatment.

  Study EGAS00001005029

• Comprehensive analysis of the abnormality of the genes in juvenile myelomonocytic leukemia

  To develop a simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia. We used the DREAM method, a method for whole genome methylation analysis using NGS, to analyze methylation profiling of patients with juvenile myelomonocytic leukemia.

  Study JGAS000292