Biology subjects

Erlacher, M.

Publications and source records attributed to Erlacher, M..

8 recordsLinked to original sources

bioRxiv2026

Hierarchical classification of hematologic malignancies using epigenetic and genetic information

Molecular testing in hematology requires different assays for disease subgroup identification, risk stratification and selection of appropriate treatment regimens. Yet, molecular tests are not necessarily standardized between diagnostic laboratories, resulting in varying turnaround times and potentially divergent results. To resolve this issue and enable single-assay molecular testing, we have developed a hierarchical classification framework that combines epigenetic and genetic data from whole genome nanopore sequencing (WGNS) with machine learning to determine disease entities, epigenetic subgroups (epitypes) and genetic aberrations in hematopoietic neoplasms. We curated DNA methylation data from 5,420 samples and trained a classifier allowing entity-level diagnostics featuring 21 conditions, including healthy controls, acute and chronic myeloid and lymphoid neoplasms. This classifier was subsequently combined with entity-specific epitype classifiers predicting 44 therapeutically or prognostically relevant states, followed by integration of genetic data. Benchmarking of the combined (epi-)genetic testing strategy using WGNS confirmed high accuracy in the detection of diagnostic groups and risk stratification, and identified diagnosis-defining molecular alterations that were not reported by standard-of-care work-up.

cancer biology↗

bioRxiv2026

TET2 loss promotes premalignant survival and clonal selection in MYC-driven B cell lymphoma

The DNA demethylase ten-eleven translocation enzyme 2 (TET2) is frequently inactivated in hematologic malignancies, yet how its loss shapes oncogene-driven transformation remains unclear. Using a mouse model in which MYC is overexpressed in the B cell lineage, driving aggressive B cell lymphoma, we show that Tet2 loss increases lymphoma penetrance and biases disease toward an IgM immunophenotype. Established lymphomas are broadly similar across genotypes, suggesting that Tet2 loss exerts much of its effects before lymphoma onset. Accordingly, Tet2 loss expands a premalignant IgM B cell subset with reduced apoptotic sensitivity and an increased frequency of BCL2BIMhi cells. Consistently, Tet2 deficient IgM B cells persist better in in vitro cultures, show increased clonogenic survival, and exhibit clonal skewing. These findings support a model in which Tet2 loss heightens MYC-driven lymphoma penetrance by promoting the survival and selection of premalignant B cells under apoptotic stress.

cancer biology↗

bioRxiv2025

Oncogenic PTPN11/SHP2 drives immune escape in juvenile myelomonocytic leukemia (JMML) through activation of ectonucleotidase/adenosine signaling

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic/myeloproliferative neoplasm of early childhood driven by RAS pathway mutations. Allogeneic hematopoietic stem cell transplantation (HSCT) is the therapy of choice for most patients. However, relapse rate is high, in patients with adverse features, frequently noted in PTPN11-mutated JMML, or in patients without evidence of graft-versus-host disease (GvHD). Here we set out to understand the mechanisms associated with oncogenic PTPN11 immune escape. Analyzing primary PTPN11-mutated JMML samples and MxCre;Ptpn11D61Y/+ mice, we observed elevated expression of immune checkpoint molecules, including ectonucleotidases CD39 and CD73 - key mediators of the adenosine pathway - on monocytic and granulocytic leukemic cells. Stimulation with GM-CSF, a central mediator of JMML pathogenesis, induced ectonucleotidases expression on granulocytes and monocytes. In contrast, MEK inhibition downstream of Ptpn11D61Y/+ reduced ectonucleotidases expression. Functionally, Ptpn11D61Y/+-mutated myeloid cells suppressed activation and proliferation of wild-type (WT) T lymphocytes, an effect recapitulated by adenosine and reversed by pharmacological CD39 inhibition with POM-1. In vivo, POM-1 treatment of MxCre;Ptpn11D61Y/+mice presenting with myeloproliferation reduced spleen size and partially restored immune responsiveness. Moreover, POM-1 induced apoptosis in murine Ptpn11D61Y/+ myeloid cells, highlighting a dual therapeutic benefit of CD39 inhibition in JMML. Together, these findings suggest that targeting the adenosine pathway may represent an immunomodulatory approach to enhance T cell-mediated control of JMML, particularly in the context of HSCT and relapse prevention.

cancer biology↗

bioRxiv2025

AURKA promotes malignant properties of neuroblastoma and is downregulated by the PP2A pathway

The role of Aurora kinase A (AURKA) in malignant transformation of sympathoadrenergic progenitors (SAPs), the cells of origin of neuroblastoma (NB), and in progression and maintenance of NB is incompletely understood. MYCN is amplified in a subset of high-risk NB cases with poor prognosis. CDKN2A, which encodes the tumor suppressors p16INK4A and p14ARF, is deleted or silenced in a subset of NB. PPP2R4 (also known as PTPA) is a key activator of the phosphatase PP2A known to suppress NB. We show that AURKA and MYCN expression decreases postnatally in murine adrenal glands, suggesting that their expression may contribute to the maintenance of SAPs. In mouse embryonic fibroblasts (MEFs), used in place of difficult-to-isolate SAPs, AURKA contributed to transformation only when MYCN was overexpressed and INK4A/ARF was depleted. In transgenic mice expressing human AURKA (hAURKA) in adrenal glands, hAURKA mRNA was present but protein was undetectable, likely due to AURKAs short half-life, possibly limiting its role in initial transformation of SAPs. However, AURKA cooperated with MYCN to promote progression of established human SH-EP NB cells lacking INK4A/ARF. In addition, AURKA expression increased during NB progression in TH-MYCN mice and correlated with poor prognosis in human NB, supporting a role for AURKA in disease progression and maintenance. CDKN2A and PPP2R4 mRNA levels also rose during NB progression in TH-MYCN mice, possibly reflecting inadequate tumor-suppressive responses. Bayesian analysis of TH-MYCN expression data supported a role for PPP2R4 in inhibiting NB maintenance. Knockout of PPP2R4 in KELLY NB cells, along with reduced mePPP2CA, the catalytic subunit of PP2A, increased AURKA protein levels, indicating that PP2A regulates AURKA abundance. Together, these findings indicate that AURKA promotes malignant properties of NB and is decreased by the PP2A pathway in NB cells

cancer biology↗

bioRxiv2025

Extended Shine-Dalgarno motifs govern translation initiation in Staphylococcus aureus

Regulation of translation initiation is central to bacterial adaptation, but species-specific mechanisms remain poorly understood. We present high-resolution mapping of translation start sites in S. aureus, revealing distinct features of initiation alongside numerous unannotated small ORFs. Our analysis, combined with cryo-EM of a native mRNA-ribosome complex, shows that S. aureus relies on extended, start codon proximal Shine-Dalgarno (SD) interactions, creating specificity against phylogenetically distant bacteria. Several natural S. aureus initiation sites are not correctly decoded by E. coli ribosomes. We identify new and conserved non-canonical start codons, whose regulatory initiation sites contain these characteristic extended SD sequence motifs. Finally, we characterize a striking example of uORF-mediated translational control in S. aureus, demonstrating that translation of a novel small leader peptide modulates expression of a key biofilm regulator. The described mechanism involves codon rarity, ribosome pausing and arginine availability, linking nutrient sensing to biofilm formation in this major human pathogen. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/660503v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1ea5094org.highwire.dtl.DTLVardef@505be5org.highwire.dtl.DTLVardef@1c14ad6org.highwire.dtl.DTLVardef@118549c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2024

Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation

The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS. Key pointsO_LIIn a mouse model for GATA2 deficiency, leukemia emerges from bone marrow failure C_LIO_LIMaladaptation to proliferative signals and chromosomal segregation defects contribute to the hematological phenotypes in GATA2 deficiency C_LI

cell biology↗

bioRxiv2023

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

Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis1. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins2-6. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease7-10. 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{blacksquare} Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. {blacksquare}The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. {blacksquare}High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). {blacksquare}RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. {blacksquare}The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.

cancer biology↗

bioRxiv2018

Checkpoint kinase 1 is essential for fetal haematopoiesis and hematopoietic stem cell survival

Checkpoint kinase 1 is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumour cells have developed a strong dependence on CHK1 for survival and hence this kinase has developed into a popular drug-target. Chk1-deficiency in mice results in blastocyst death due to G2/M checkpoint-failure showing that it is an essential gene and may be difficult to target therapeutically without side-effects. Here, we show that chemical inhibition of CHK1 kills murine hematopoietic stem and progenitor cells (HSPCs) as well as human CD34+ HSPCs by the induction of BCL2-regulated but p53-independent apoptosis. Moreover, Chk1 is essential for stem cell survival and definite hematopoiesis in the mouse embryo. Remarkably though, cell death inhibition in hematopoietic stem cells (HSC) cannot restore blood cell formation in utero as Chk1 loss causes severe DNA damage that ultimately prevents HSC expansion. Our findings establish a previously unrecognized role for CHK1 in establishing hematopoiesis; they also suggest adverse effects of therapeutic CHK1-inhibtion, particularly under conditions forcing stem cells out of dormancy, such as chemotherapy-induced myelosuppression.

developmental biology↗