Joschka Hey

German Cancer Research Center

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Christoph Plass

German Cancer Research Center

Pavlo Lutsik

KU Leuven

Dieter Weichenhan

Epigenomics (Germany)

Shimrit Mayer

Weizmann Institute of Science

Coral Halperin

Weizmann Institute of Science

Ruth Scherz‐Shouval

Weizmann Institute of Science

Yaniv Stein

Weizmann Institute of Science

Daniel B. Lipka

German Cancer Research Center

Maximilian Schönung

German Cancer Research Center

Mark Hartmann

National Center for Tumor Diseases

Cooperative Institutions

Heidelberg University

134

German Cancer Research Center

123

Epigenomics (Germany)

University Hospital Heidelberg

DKFZ-ZMBH Alliance

National Center for Tumor Diseases

Deutschen Konsortium für Translationale Krebsforschung

University of Freiburg

University Medical Center Freiburg

German Center for Lung Research

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Altered enhancer-promoter interaction leads toMNX1expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Dieter Weichenhan Anna Riedel Etienne Sollier Umut H. Toprak Joschka Hey

Abstract Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners ( MNX1 and ETV6 ) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6 . The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML. Key points Expression analysis of over 1500 pediatric AML samples demonstrates MNX1 expression as a universal feature of t(7;12)(q36;p13) AML as well as in rare cases without t(7;12)(q36;p13) MNX1 is activated by an enhancer-hijacking event in t(7;12)(q36;p13) AML and not, as previously postulated, by the creation of a MNX1 :: ETV6 oncofusion gene.

Breakpoint

10.1101/2023.09.13.557546

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Supplementary Table from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma

Coral Halperin Joschka Hey Dieter Weichenhan Yaniv Stein Shimrit Mayer

Supplementary Table from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma

RUNX1

10.1158/0008-5472.22432535

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High-resolution transcriptomic and epigenetic profiling across disease stages identifies novel regulators of COPD phenotypes.

Maria Llamazares Prada Uwe Schwartz Stephanie Pohl Mandy Richter Michael Schüller

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. For these to be developed, better understanding of molecular mechanisms driving disease onset is required. Considering the environmental cause of COPD, we hypothesized that the disease will be associated with altered epigenetic signalling in lung cells. Using whole-genome bisulfite sequencing, we generated genome-wide DNA methylation maps at single CpG resolution of parenchymal fibroblasts and alveolar type 2 (AT2) cells across COPD stages. We demonstrate that epigenetic landscape is severely changed in COPD, with epigenetics changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA sequencing of matched samples showed dysregulation of pathways involved in proliferation, cell differentiation, extracellular matrix organisation, inflammation and viral immunity. Excitingly, we identify epigenetic changes and gene subsets dysregulated already in mild COPD, providing unique insight into early disease. Integration of profiling data identified epigenetically regulated pathways and candidate drivers of COPD phenotypes. We uncover a strong anticorrelation between gene expression and promoter methylation in AT2 cells, suggesting that aberrant transcriptional changes might be regulated by DNA methylation. Interferon (INF) signalling was the top upregulated pathway in AT2 cells with the strongest association to DNA methylation loss in the promoters of downstream genes. Using DNA methylation inhibitors and CRISPR-based epigenetic editing in lung cell lines we validated the link between methylation loss and activation of IFN-signalling.

Epigenomics

CpG site

Bisulfite sequencing

10.1183/23120541.lsc-2022.202

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The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13

Blood (2021)

Costanza Zanetti Rahul Kumar Joscha Ender Parimala Sonika Godavarthy Mark Hartmann

CXCL13

CXCR5

10.1182/blood.2021011557

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Citations (25)

A Unique Signature for Cancer‐Associated Fibroblasts in Melanoma Metastases

Pigment Cell & Melanoma Research (2025)

Saskia Tauch Joschka Hey Bettina Kast Nicolas Gengenbacher Lena Weiß

Cancer-associated fibroblasts (CAFs) represent a central cell population of the tumor microenvironment (TME). Recently, single-cell RNA-sequencing (scRNA-seq) analyses of primary tumors of different cancer entities yielded different classifications of CAF subsets underscoring the heterogeneity of CAFs within the TME. Here, we analyzed the transcriptional signatures of approximately 8400 CAFs and normal fibroblasts by scRNA-seq and compared genetic profiles of CAFs from murine melanoma primary tumors to CAFs from corresponding melanoma lung metastases. This revealed distinct subsets for primary tumor and metastasis-specific CAF populations, respectively. Combined with the spatial characterization of metastasis CAFs at the RNA and protein level, scRNA analyses indicate tumor-dependent crosstalk between neutrophils and CAFs, mediated via SAA3 and IL1b-related signaling pathways, which can be recapitulated in vitro. Analyzing tissue sections of human patient samples, this interaction was found to be present in human melanoma metastasis. Taken together, our data highlight unique characteristics of metastasis CAFs with potential therapeutic impact for melanoma metastasis.

Cancer-Associated Fibroblasts

10.1111/pcmr.70002

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Oncogenic RAS-Pathway Activation Drives Oncofetal Reprogramming and Creates Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Mark Hartmann Maximilian Schönung Jovana Rajak Valentin Maurer Ling Hai

Abstract Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis 1 . Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins 2–6 . In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease 7–10 . To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo . In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. Highlights ▪ Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. ▪ The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. ▪ High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). ▪ RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. ▪ The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.

Juvenile myelomonocytic leukemia

Reprogramming

Epigenomics

10.1101/2023.10.27.563754

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ONCO-FETAL REPROGRAMMING DRIVES HIGH-RISK JUVENILE MYELOMONOCYTIC LEUKEMIA, WHICH CAN BE TARGETED BY ANTI-CD52 TREATMENT

EJC Paediatric Oncology (2023)

Mark Hartmann Maximilian Schönung Jovana Rajak Joschka Hey Valentin Maurer

Juvenile myelomonocytic leukemia

Reprogramming

10.1016/j.ejcped.2023.100065

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Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

Nature Communications (2021)

Joschka Hey Michelle T. Paulsen Réka Tóth Dieter Weichenhan Simone Butz

Abstract Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease ( Scnn1b -transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b -transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b -transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.

Reprogramming

efferocytosis

Macrophage polarization

10.1038/s41467-021-26777-9

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Citations (51)

High‐resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD

The EMBO Journal (2023)

Uwe Schwartz Maria Llamazares Prada Stephanie Pohl Mandy Richter Raluca Tamas

Abstract Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome‐wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked to fibroblast repair processes using phenotypic screens. Our study provides high‐resolution multi‐omic maps of HLFs across COPD stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic lung diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

CpG site

Epigenomics

10.15252/embj.2022111272

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Citations (10)

The Influence of the Age of the Bone Marrow Microenvironment on Leukaemia Progression

Blood (2019)

Costanza Zanetti Joscha Ender Mark Hartmann Joschka Hey Parimala Sonika Godavarthy

Homing (biology)

10.1182/blood-2019-122797

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Citations (0)