Biology subjects

Straube, J.

Publications and source records attributed to Straube, J..

10 recordsLinked to original sources

bioRxiv2026

Dnmt3a-mutant Leukemia Stem Cells evade chemotherapy through enforced quiescence in Npm1c-Flt3ITD Acute Myeloid Leukemia

Concurrent mutations in DNMT3A, NPM1, and FLT3 define a high-risk subtype of acute myeloid leukemia (AML) associated with increased relapse risk and inferior survival following standard chemotherapy. However, the mechanisms by which DNMT3A mutations promote treatment resistance in NPM1c-FLT3ITD AML remain unclear. Using genetically engineered murine models of Npm1c-Flt3ITD AML with or without Dnmt3aR878H (homologous to human DNMT3AR882H), we demonstrate that Dnmt3aR878H promotes chemotherapy resistance through epigenetic regulation of leukemia stem cell (LSC) quiescence. Integrated transcriptomic and epigenetic profiling revealed coordinated remodeling of DNA methylation and chromatin accessibility in LSC-enriched populations, characterized by preferential hypomethylation and increased accessibility at loci associated with stemness and quiescence programs. These data were confirmed in human DNMT3AR882H-NPM1c-FLT3ITD AML datasets with enrichment of quiescence-associated and stem cell enriched transcriptional programs. Conversely, Dnmt3a-mutant LSCs retained sensitivity to the cell-cycle independent regimen venetoclax plus azacitidine, but residual LSCs exhibited transcriptional plasticity and reversion to a de-differentiated state. We have identified LSC heterogeneity spanning primitive hematopoietic stem cell (HSC)-and progenitor-like states and our data demonstrate preferential maintenance of a quiescent HSC-like LSC subpopulation in Dnmt3aR878H-mutant AML following chemotherapy treatment. Pharmacologic induction of cell-cycle entry using pegylated interferon (pegIFN) disrupted the quiescent LSC state and restored chemotherapy sensitivity, identifying quiescence as a reversible and therapeutically actionable mechanism of resistance. These findings identify DNMT3A-mediated epigenetic regulation of LSC quiescence as a conserved mechanism of standard chemotherapy resistance and position therapeutic reactivation of quiescent LSCs as a promising strategy to overcome chemotherapy resistance and improve outcomes in high-risk DNMT3A-mutant AML.

cancer biology↗

bioRxiv2026

Climate-driven in-situ trait variation in an annual ruderal grass across Europe

O_LIPlant functional traits link environmental conditions to plant performance and adaptation. Growing evidence shows that in-situ intraspecific trait variation can be as important as differences between species, yet large intraspecific datasets measured in situ are rare. While most studies focused on plant morphological traits, contents of elemental nutrients in the seeds received much less attention so far. C_LIO_LIWe conducted a large-scale in-situ study of the widespread ruderal grass Hordeum murinum. We sampled 2070 individuals from 207 populations from a large part of the native range in Europe and Northern Africa. In-situ, we measured seed ripening phenology and morphological traits, and analyzed the content of elemental nutrients in the seeds. C_LIO_LIWe found that Hordeum murinum grew larger, produced seeds later, and had heavier seeds in colder and wetter areas. Plants in denser vegetation were taller with heavier seeds but formed fewer spikes. Seed nutrient content generally declined with seed weight and was mainly driven by climate. Soil conditions had only minor effects on plant traits and seed nutrients. Population identity explained much of the variation, indicating a possible genetic component. C_LIO_LISynthesis: Our findings provide a comprehensive view of Hordeum murinum responding to environmental gradients across its European distribution. Climatic variables, especially temperature, are key drivers for reproductive success and seed nutrient content, while local environments, such as biotic pressures, are more critical for growth-related traits. These patterns indicate that H. murinum modulates its growth and reproductive investment along environmental gradients, balancing phenology, stress tolerance, and limited competitive capacity. C_LI

ecology↗

bioRxiv2025

Single cell long-read genotyping of transcriptomes reveals discrete mechanisms of clonal evolution in post-myeloproliferative neoplasm acute myeloid leukemia.

Myeloproliferative neoplasms (MPNs) are caused by acquired mutations in hematopoietic stem and progenitor cells (HSPCs). The acquisition of additional mutations like TP53 and the overall mutational burden influence a patients risk of disease progression toward lethal post-MPN acute myeloid leukemia (AML). Recent technological advancements in linking single-cell gene expression with genotype have improved our understanding of tumor heterogeneity. However, current methodologies have limitations in simultaneously genotyping low-expression genes (such as JAK2) alongside other pathogenic loci. To address this, we developed a novel long read genotyping pipeline of cDNA transcripts called LOTR-Seq, which can genotype the full length of expressed transcripts of 30 genes at once. Using LOTR-Seq, we genotyped HSPCs at the JAK2V617 locus in 9,075 single cells from eight patients with chronic phase MPN (CP-MPN) and in 5,016 cells from four patients with post-MPN AML. We then linked the mutations to the single cell transcriptome of 29,712 JAK2V617F-driven CP-MPN cells and 16,895 post-MPN AML cells. In our analysis of post-MPN AMLs, we identified nine mutated loci across six genes (JAK2, IDH1/2, TP53, SRSF2, U2AF1) and linked these mutations to specific transcriptional phenotypes. Overall, LOTR-Seq provides novel insights into the evolution of post-MPN AML.

cancer biology↗

bioRxiv2023

A transient modified mRNA encoding Myc and Cyclin T1 induces cardiac regeneration and improves cardiac function after myocardial injury

Cardiac injury, such as myocardial infarction (MI), results in permanent loss of cardiomyocytes and in many cases heart failure. Transgenic expression of the pro-proliferative transcription factor Myc and Cyclin T1 can drive substantial adult cardiomyocyte proliferation to replace lost cardiomyocytes. Herein, we show that Myc and Cyclin T1 induced cardiomyocyte proliferation leads to myocardial repair and functional (long-term) recovery post-MI in mice. To provide a more translational approach, we developed modified mRNA (modRNA) encoding Myc-Ccnt1 as a transient and non-integrating strategy for regeneration. One dose of Myc-Ccnt1 modRNA is sufficient to transiently drives cardiomyocyte proliferation in human pluripotent stem cell-derived cardiomyocytes and a mouse MI model, where it leads to better heart function. Using single nuclei sequencing and proteomics, we show this was functionally mediated by transcriptional activation of cell-cycle regulating genes, which ultimately results in mitosis and cytokinesis of cardiomyocytes. Collectively, these findings indicate that Myc-Ccnt1 modRNA has the potential to be an effective regenerative therapeutic.

molecular biology↗

bioRxiv2023

Imetelstat-Mediated Alterations in Fatty Acid Metabolism To Induce Ferroptosis As Therapeutic Strategy for Acute Myeloid Leukemia

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft (PDX) resource, and perform integrated genomics, transcriptomics, and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized Phase II-like preclinical trial in PDX, imetelstat effectively diminishes AML burden, and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing significant disease control in AML.

cancer biology↗

bioRxiv2023

CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites.

Children in malaria-endemic regions can experience multiple Plasmodium infections over a short period of time, with in vitro CD4+ T cell recall responses becoming more regulatory with increasing age and exposure. This suggests that repeated infection qualitatively changes CD4+ T cells, although the heterogeneity and dynamics of these responses await systematic analysis in vivo. Here, we examined TCR transgenic PbTII and polyclonal CD4+ T cells during Plasmodium re-infection in mice, in conjunction with scRNA-seq/TCR-seq and spatial transcriptomics at near single-cell resolution. PbTII cells gave rise to multiple antigen-experienced states in different areas of the spleen after primary infection and antimalarial treatment, including ongoing GC responses and T-cell zone memory. Upon re-infection, Th1-memory PbTII cells initiated a rapid effector response prior to proliferating, while GC Tfh cells of the same antigen specificity were entirely refractory within the same organ. Transcriptome dynamic modelling and network analysis of Th1 recall revealed a biphasic wave of RNA processing that firstly preceded immune effector transcription, and later accompanied cellular proliferation. Importantly, Th1 recall constituted a partial facsimile of primary Th1 responses, with no unique genes amongst the small subset of those upregulated upon re-infection. Finally, we noted a similar spectrum of antigen-experienced states and recall dynamics by polyclonal CD4+ T cells with diverse TCRs. Therefore, during re-infection with Plasmodium, persisting GC Tfh cells remained unaltered transcriptionally, Tcm/Tfh-like cells exhibited minimal proliferation, and Th1-memory cells displayed a rapid, proliferating IL-10-producing Tr1 response consistent with a shift towards immune-regulation. These data highlight a broad spectrum of simultaneous CD4+ T cell responses that occur in the spleen during re-infection with malaria parasites. HighlightsO_LISplenic TCR transgenic CD4+ T cells are highly heterogeneous prior to re-infection. C_LIO_LIPersisting GC Tfh cells are refractory to re-activation during re-infection. C_LIO_LITh1-memory cells rapidly upregulate RNA processing prior to effector function and proliferation. C_LIO_LITh1-recall is an imperfect but faithful facsimile of primary Th1 responses. C_LIO_LIA spectrum of recall states is observed in polyclonal CD4+ T cells with diverse TCRs. C_LI

immunology↗

bioRxiv2023

Oncogenic drivers dictate immune control of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression has not been investigated. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML. Statement of SignificanceThe endogenous immune response against acute myeloid leukemia (AML) is determined by leukemia-specific oncogenic driver mutations. Mutant Nras drives immunological selection of AML.

cancer biology↗

bioRxiv2022

An inosine triphosphate pyrophosphatase safeguards nucleic acids from aberrant purine nucleotides and prevents a constitutive salicylic acid response

- In plants, inosine is enzymatically introduced in some tRNAs but not in other RNAs or DNA. Nonetheless, our data show that RNA and DNA from Arabidopsis thaliana contain (deoxy)inosine, probably derived from non-enzymatic adenosine deamination in nucleic acids and usage of (deoxy)inosine triphosphate (dITP and ITP) during nucleic acid synthesis. - We combined biochemical approaches, sample preparation and LC-MS, as well as RNA-Seq to characterize a plant INOSINE TRIPHOSPHATE PYROPHOSPHATASE (ITPA) from Arabidopsis thaliana, which is conserved in many organisms, and investigated the sources of deaminated purine nucleotides in plants. - ITPA dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates. ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated (deoxy)inosine content in DNA and RNA, as well as salicylic acid (SA) accumulation, early senescence and upregulation of transcripts associated with immunity and senescence. Cadmium-induced oxidative stress leads to more ITP in the wildtype, and this effect is enhanced in itpa mutants, suggesting that ITP originates from ATP deamination. - ITPA is part of a molecular protection system, preventing accumulation of (d)ITP, its usage for nucleic acid synthesis, and probably nucleic acid stress leading to SA accumulation, stress gene induction and early senescence.

plant biology↗

bioRxiv2021

Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity

ObjectiveAdoptive regulatory T cell (Treg) therapy is being trialled for treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies. MethodsThrough a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity. ResultsHigh-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro-inflammatory Th17-like phenotype and accumulate in the blood of UC patients. Dysregulation on CD49f Treg subsets in UC patients correlate with disease activity. ConclusionOverall our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.

immunology↗

bioRxiv2019

Transcriptome Dynamics Reveals Progressive Transition from Effector to Memory in CD4+ T cells.

CD4+ T cells are repositories of immune memory, conferring enhanced immunity to many infectious agents. Studies of acute viral and bacterial infection suggest that memory CD4+ T cells develop directly from effectors. However, delineating these dynamic developmental pathways has been challenging. Here, we used high-resolution single-cell RNA-seq and temporal mixture modelling to examine the fate of Th1 and Tfh effector cells during non-lethal Plasmodium infection in mice. We observed linear Th1 and Tfh pathways towards memory, characterized by progressive halving in the numbers of genes expressed, and partial transcriptomic coalescence. Low-level persisting infection diverted but did not block these pathways. We observed in the Th1-pathway a linear transition from Th1 through a Tr1 state to TEM cells, which were then poised for Th1 re-call. The Tfh-pathway exhibited a modest Th1-signature throughout, with little evidence of Tr1 development, and co-expression of TCM and memory Tfh markers. Thus, we present a high-resolution atlas of transcriptome dynamics for naive to memory transitions in CD4+ T cells. We also defined a subset of memory-associated genes, including transcription factors Id2 and Maf, whose expression increased progressively against the background of transcriptomic quiescence. Single-cell ATAC-seq revealed substantial heterogeneity in chromatin accessibility in single effectors, which was extensively, though incompletely reset and homogenized in memory. Our data reveal that linear transitions from effector to memory occur in a progressive manner over several weeks, suggesting opportunities for manipulating CD4+ T cell memory after primary infection.\n\nHighlightsO_LIscRNA-seq reveals progressive transition from effector to memory in CD4+ T cells.\nC_LIO_LITranscriptome dynamics suggest linear not branching models for memory development.\nC_LIO_LIA subset of genes associates with gradual onset of CD4+ T cell memory.\nC_LIO_LITh1/Tfh predisposition varies among clonotypes with identical antigen-specificity.\nC_LIO_LIscATAC-seq uncovers non-coding \"memory\" elements in the genome.\nC_LI

immunology↗