Biology subjects

Scherer, M.

Publications and source records attributed to Scherer, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma

Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

cancer biology↗

bioRxiv2026

Human cytomegalovirus antagonizes SMC5/6 driven genome silencing via UL35 instituted proteasomal degradation of SLF2

Recent studies demonstrated that the structural maintenance of chromosomes complex 5/6 (SMC5/6) acts as an important antiviral restriction factor that silences episomal DNA. Consequently, viruses have evolved strategies to antagonize this defence system. Interestingly, it was shown that SMC5/6-mediated silencing of extrachromosomal DNA depends on its recruitment to PML nuclear bodies which is mediated by a protein termed SMC5/6 localization factor 2 (SLF2). Since human cytomegalovirus (HCMV) dissociates PML nuclear bodies (PML-NBs) during the first hours of infection, we asked for the fate of SMC5/6 components during the HCMV replicative cycle. We first investigated the expression levels of SMC5/6 core components at the onset of HCMV infection and found that they were not downregulated by HCMV. Instead, we observed a distinct decrease of SLF2 protein levels which correlated with a complete dispersal of the SMC5/6 complex from PML-NBs. This was also observed after infection with UV inactivated HCMV and could not be blocked by cycloheximide treatment suggesting the involvement of an imported structural component of the virion. While we could exclude a role of the HCMV tegument protein pp71 (UL82), a targeted screen identified the tegument protein UL35 as being required and sufficient for proteasomal degradation of SLF2. In line with these results, SLF2 levels remained stable after infection with a recombinant HCMV harbouring a stop codon within the UL35 gene region and this correlated with a defect in the onset of HCMV immediate early gene expression. Furthermore, we observed an enhanced recruitment of SMC5/6 to PML-NBs and an overall increase in the association of parental viral genomes with SMC5/6 containing PML-NBs in the absence of UL35. Congruently, siRNA mediated depletion of SLF2 resulted in a reversal of this phenotype. This strongly suggests that UL35 serves as a novel viral SLF2 antagonist to prevent the initial silencing of incoming viral genomes by SMC5/6. Author summaryHuman cytomegalovirus (HCMV) is an important human pathogen which establishes a life-long persistent infection. Previous research revealed that host intrinsic defense mechanisms can silence HCMV gene expression and thereby foster latency. However, during lytic infection, viral effector proteins like the structural protein pp71 (UL82) and the viral immediate-early protein IE1 act as antagonists of this defense. Here, we report on the identification of a novel antagonist of host-mediated viral gene silencing which targets the SMC5/6 complex. SMC5/6 belongs to a highly conserved family of protein complexes that act as loop extrusion machines to facilitate the folding of chromatin. While SMC5/6 core factors were not attacked by HCMV, we found that the SMC5/6 associated protein SLF2 was degraded by the viral tegument protein UL35, that is imported into infected cells. This abrogates the accumulation of SMC5/6 at PML nuclear bodies which compromises the entrapment of viral genomes in these subnuclear structures. Since SLF2 is also important for genome stability and pathogenic variants of SLF2 cause the neurodevelopmental disease Atelis syndrome, we speculate that depletion of this factor via a viral tegument protein may also contribute to DNA damage induced during congenital HCMV infection.

microbiology↗

bioRxiv2026

An engineered biosensor for the fast and accurate detection of terephthalate

Accelerating the development of enzymatic degradation of polyesters such as poly(ethylene terephthalate) (PET) and poly(butylene terephthalate) (PBT) requires a rapid and parallelizable detection method. We developed a protein-based biosensor for the fast and accurate quantification of the PET and PBT degradation product, terephthalate (TPA), which we named TPAsense. Engineering TPAsense required overcoming low thermal stability and aggregation of the initial construct by introducing stabilizing mutations without disrupting the binding affinity to TPA. The sensor performance was validated by screening for the PBT degrading activity of a Leaf-branch Compost Cutinase (LCC) mutant library and comparing with liquid chromatography data. TPAsense detects nanomolar concentrations of TPA enabling shorter incubation times for screening workflows. In addition, a comparative analysis of PETase and PBTase kinetics was performed with TPAsense. Finally, we demonstrated the detection of PET microplastic in samples from a wastewater treatment plant by combining the biosensor and a PETase. TPAsense offers a platform to accelerate PETase and PBTase development for plastic waste recycling and detection of microplastic in the environment.

biochemistry↗

bioRxiv2025

Inconsistent Subthalamic Beta Expression in the Local Field Potential amid In- and Anti-Phasic Neuronal Bursts.

BackgroundElevated beta (12-32 Hz) activity in the local field potential (LFP) of the subthalamic nucleus (STN) is a hallmark of Parkinsons disease and closely tied to synchronized spiking. Albeit the biomarkers prevalence has not been independently and reliably assessed, it is employed to guide deep brain stimulation (DBS) lead implantation. Likewise, beta is under investigation to inform DBS programming and adaptive DBS. This study assesses the applicability of these efforts by quantifying the biomarkers prevalence and investigating its relationship to synchronized beta-bursting neurons. MethodsSTN LFP and spiking activity of n = 156 patients with Parkinsons disease from six DBS centers recorded via microelectrodes was examined. Spectral peaks in the LFPs were classified and the absence of artifacts confirmed. The distribution of phase angles between beta LFP and spiking of individual beta-bursting neurons were explored. FindingsBilateral beta LFP expression was observed in 47{middle dot}25% of patients, and in 65{middle dot}59% of hemispheres. LFP-synchronized neuronal spiking clustered in two-thirds of neurons at a primary and in one-third at a secondary LFP phase (182{middle dot}84{degrees} phase shifted). This applied on the group level and for individual patients across different DBS centers. InterpretationBeta-informed approaches mandate reliable biomarker expression, a requirement not met by slightly more than half of herein investigated patients. This is particularly troublesome for intraoperative guidance wherein the cause of biomarker absence, including DBS lead misplacement or a balanced ratio of phasic and antiphasic spiking neurons, cannot be determined, decreasing insight and increasing doubt. Although beta LFPs remain a valuable biomarker, routine clinical practice should not rely on beta alone; instead, multiple biomarkers (i.e. beta-gamma coupling, finely tuned gamma and/or cortico-cortical beta-band coupling) should be evaluated simultaneously to increase robustness. FundingMaximilian Scherer received funding from the Alexander von Humboldt-Foundation. Thomas Koeglsperger has been supported by the Munich Clinician Scientist Program.

neuroscience↗

bioRxiv2025

Integrative spatial and multi-omic profiling in bladder cancer links L1 retrotransposition to extrachromosomal DNA, genomic instability, and viral mimicry response

Bladder cancer is one of the most frequent cancers and shows high recurrence rates. Despite recent advances, key knowledge gaps remain in understanding the molecular mechanisms of disease progression, which would support the development of early detection methods and effective personalized treatments. We apply integrated multi-omics and spatial analyses in a cohort of 49 bladder cancer patients to comprehensively profile genetic, epigenetic, transcriptomic, and spatial features of bladder cancer, alongside cell-free DNA blood analysis. Combining low-pass whole-genome cell-free DNA sequencing, Oxford Nanopore long-read tumor DNA sequencing, RNA-sequencing, and spatial transcriptomics, we provide insights into molecular alterations driving bladder cancer. We show frequent somatic LINE-1 (L1) insertions, with up to more than 500 insertions per tumor. We find that L1 insertions are active and occur early in bladder cancer development. We link aberrant somatic L1 insertion in bladder cancer with downstream genomic rearrangements and chromosomal instability, with an excess of structural variants and extrachromosomal DNA (ecDNA) in patients with particularly high L1 counts. By detecting ecDNA within tissue architecture using spatial transcriptomics, we identify the localization of ecDNA to distinct spatial clusters with differential expression of APOBEC3B and immune response pathways. These results, combined with replication timing analysis and gene set enrichment analysis (GSEA), offer evidence for the previously hypothesized viral mimicry response to L1 retrotransposition, mediated via APOBEC3B-editing, the cGAS-STING pathway, and RIG-I and MDA5 responses.

cancer biology↗

bioRxiv2025

Optimizing stability in dynamic small-molecule binding proteins

The function of dynamic proteins is determined by the stability of distinct conformational states and the energy barriers that separate these states. For most dynamic proteins, the molecular details of the energy barriers are not known, implying a fundamental limit to the ability of protein design methods to engineer beneficial mutations without disrupting activity. We hypothesized that designing mutations that are compatible with structurally distinct equilibrium conformations may enable reliable stability design. We focus on periplasmic binding proteins (PBPs), a superfamily of dynamic proteins that change conformation from open to closed states in response to binding their small-molecule ligands. We find that the evolutionary constrained space of allowed mutations computed for one conformation is incompatible with the other. Therefore, putative conformational hinge points and interface residues were additionally constraint, and incompatible mutations were filtered out. Starting from four different PBPs, we designed a total of 16 stabilized variants with 7-28 mutations each. Our results show that design based on a single conformation with evolutionary constraints is not sufficient to maintain wild type-like binding affinity. Conversely, using a subset of mutations compatible with both conformations and structural constraints reliably enhances thermal stability while mitigating trade-offs in ligand binding. Our work demonstrates a straightforward method for the one-shot stabilization of dynamic proteins, which is critically required to generate robust starting points for thermostable and responsive biosensors.

biochemistry↗

bioRxiv2025

Exonuclease ISG20 inhibits human cytomegalovirus replication by inducing an innate immune defense signature

ISG20 is an interferon-regulated protein that exhibits RNase activity thereby inhibiting the replication of a broad spectrum of RNA viruses. By single cell RNA sequencing, we identified ISG20 as an antiviral factor for human cytomegalovirus (HCMV) as it was upregulated in a population of HCMV-resistant cells. In accordance with an antiviral role on herpesviruses, overexpression of ISG20 in primary human fibroblasts led to reduced HCMV and HSV-1 replication, while knockdown of ISG20 enhanced virus growth. In Western blot kinetics, we observed that inhibition of HCMV replication by ISG20 occurs at the early stage of infection which correlated with reduced amounts of viral early and late transcripts. However, neither the half-life of viral and cellular RNAs nor of viral DNA was decreased in ISG20-expressing cells, indicating that ISG20 does not exert its antiviral effect via a degradation of RNAs or DNA. Instead, RNA-seq analysis revealed an innate immune defense signature upon ISG20 expression that comprised the upregulation of a distinct set of interferon stimulated genes (ISGs), zinc finger proteins (ZNFs) and of transposable elements (TEs). Our data indicate that this gene signature augments both IFN production and response of the host cell. Consistently, the JAK-STAT inhibitor ruxolitinib rescued HCMV gene expression in ISG20-expressing cells. We conclude that ISG20 induces a so far unprecedented immune defense signature that serves to amplify the IFN-mediated host cell defense thus explaining its broad antiviral activity.

microbiology↗

bioRxiv2024

Personalized Medicine for Meningiomas: Drug Screening on Tumor Organoids Exposes Therapeutic Vulnerabilities to HDAC1/2i Panobinostat

Managing aggressive meningiomas remains challenging due to limited treatment options besides surgical tumor removal and radiotherapy. To identify novel therapies for aggressive meningiomas, we established a multi-step drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas. In vitro screening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissues genotype and phenotype. Individual drug responses were assessed in TOs from 60 molecularly characterized meningioma cases. Especially the FDA-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through HDAC1/2 inhibition. In addition, treatment in an orthotopic in vivo model revealed a significantly improved survival. In a heavily pretreated patient suffering from an anaplastic meningioma, oral panobinostat treatment could delay the tumor growth rate. In search of the molecular mechanism underlying a potential intrinsic panobinostat resistance, we identified upregulation of the HDAC8-TGF{beta}-EMT axis in the TO model and subsequent HDAC8 depletion substantially increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for a more effective treatment of clinically aggressive meningiomas and help to advance our understanding of counteracting resistance mechanisms. One Sentence SummaryThis study provides strong in vitro, in vivo, ex vivo, and patient evidence for the efficacy of the HDACi panobinostat to treat clinically aggressive meningiomas and uncovered a potential intrinsic resistance mechanism by activation of the HDAC8-TGF{beta}-EMT axis.

cancer biology↗

bioRxiv2024

Poxviruses induce a nuclear environment in the cytoplasm to promote viral replication

The family Orthopoxviridae comprises several members that can cause disease in humans, including Small-, Cow-, Camel-, and Monkeypoxvirus. In 2022 a global outbreak of the zoonotic monkeypoxvirus started with human- to- human transmission and more than 100 000 global cases in all continents. This outbreak emphasizes the need for more basic research to get a better understanding of poxvirus biology. We characterized the cellular response to poxvirus infection and performed bulk RNA-sequencing of primary human fibroblasts infected with Modified-Vaccinia Ankara Virus (MVA), Vaccinia Virus, Cowpoxvirus, Camelpoxvirus and 4 different Monkeypoxvirus isolates (clade 1-2b) at various time points to compare the transcriptome of infected cells. We could demonstrate that MVA infection leads to a potent activation of innate immune genes that is absent in other samples. Camelpoxvirus infection results in a strong activation of NF-kB signaling 2h post infection whereas all other viruses inhibit NF-kB activation. In addition, we observed transport of cellular proteins like histone H1, lamin A/C, emerin and topoisomerase II A/B from the nucleus into cytoplasmic poxvirus factories. This correlates with drastic structural changes inside the nucleus in electron microscopy, namely formation of nuclear filaments, indicating intensive remodeling of the nuclear architecture. Accordingly, inhibition of topoisomerase using the clinically approved topoisomerase inhibitor epirubicin reduced viral replication of several Mpox strains. We observe a reduction of viral replication by epirubicin in cells of human and mouse species, indicating that the recruitment of TOP2B into viral factories is crucial for MPXV replication.

microbiology↗

bioRxiv2024

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a block in differentiation and accelerated proliferation of myeloid progenitor cells. Genes encoding for epigenetic regulators are among the most frequent targets for mutations and structural variations in AML, giving rise to profound epigenetic heterogeneity between and within tumors. Deletions of chromosome 5q [del(5q)] are among the most common copy number alterations in AML and are associated with extremely poor clinical outcome and therapy resistance, however the mechanisms linking del(5q) to leukemic progression are not understood. Analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, we discovered that del(5q) AML is an epigenetically distinct subgroup characterized by a signature of DNA hypermethylation, which we propose may be linked to dysregulation of H3K9me1/2 and overexpression of the leukemic stem cell marker, DNMT3B. Interrogation of the minimally deleted 5q region highlighted the H3K9me1/2 demethylase KDM3B as a likely target for haploinsufficiency in this subgroup. Our data suggest that del(5q) AML should be reconsidered as an epigenetically dysregulated subgroup, driven by heterozygous loss of KDM3B, and that the resulting imbalance of H3K9me1/2 may contribute to the progression of these aggressive leukemias.

cancer biology↗

bioRxiv2024

Ice and air: Visualisation of freeze-thaw embolism and freezing spread in young L. tulipifera leaves

Spring freezing is an unforgiving stress for young leaves, often leading to death, with consequences for tree productivity and survival. While both the plant water transport system and living tissues are vulnerable to freezing, we do not know whether damage to one or both of these systems causes death in leaves exposed to freezing. Whole saplings of Liriodendron tulipifera were exposed to freezing and thawing trajectories designed to mimic natural spring freezes. We monitored the formation of freeze-thaw xylem embolism and damage to photosynthetic tissues to reveal a predictable progression of ice formation across the leaf surface that is strongly influenced by leaf vein architecture, notably the presence or absence of bundle sheath extensions. Our data also show that freeze-thaw embolism occurs only in the largest vein orders where mean vessel diameter exceeds 30{micro}m. With evidence of both freeze-thaw embolism and damage to photosynthetic tissue, we conclude that this dual-mode lethality may be common among other wide-vesseled angiosperm-leaves, potentially playing a role in limiting geographic distributions, and show that bundle sheath extensions may stall or even prevent freezing spread. HighlightBoth ice and air lead likely lead to death in young L.tulipfera leaves exposed to freezing, with the spread of both governed by physical characteristics of these leaves.

physiology↗

bioRxiv2024

FiNNpy 2.0: Fast MEG source reconstruction

Herein, we present the 2.0 update of FiNNpy, which expands the toolkits initial scope from the analysis of multi-site electrophysiological activity to track information propagation to include source reconstruction capability for MEG signals. Following the toolkits de- sign guidelines, the new functionality has been optimized towards minimal resource consumption, making source reconstruction much faster, especially when executed in a parallelized fashion. Furthermore, several quality-of-life aspects are introduced to support source reconstruction, such as grouping source-space activity into cortical areas, a cohesive documentation & in-code extensive literature references, and wrapping of previously terminal exclusive functions of FreeSurfer.

neuroscience↗

bioRxiv2024

Development, validation and application of an LC-MS/MS method quantifying free forms of the micronutrients queuine and queuosine in human plasma using a surrogate matrix approach

Queuosine (Q) is a hypermodified 7-deaza-guanosine nucleoside exclusively synthesized by bacteria. This micronutrient and its respective nucleobase form queuine (q) are salvaged by humans either from gut microflora, or digested food. Depletion of Q-tRNA in human or mouse cells causes protein misfolding that triggers endoplasmic reticular stress and activation of the unfolded protein responses. In vivo, this reduces neuronal architecture of the mouse brain affecting learning and memory. Herein, a sensitive method for quantifying free q and Q in human blood was developed, optimised and validated. After evaluating q/Q extraction efficiency in several different solid-phase sorbents, Bond Elut PBA (phenylboronic acid) cartridges were found to have the highest extraction recovery for q (82%) and Q (71%) from pooled human plasma. PBS with 4% BSA was used as surrogate matrix for method development and validation. An LC-MS/MS method was validated across the concentration range of 0.0003 - 1 {micro}M for both q and Q, showing excellent: linearity (r2 = 0.997 (q) and r2 = 0.998 (Q)), limit of quantification (0.0003 {micro}M), accuracy (100.39% - 125.71%) and precision (CV% < 15.68%). In a sampling of healthy volunteers (n = 44) there was no significant difference in q levels between male (n = 14; mean = 0.0068 {micro}M) and female (n = 30; mean = 0.0080 {micro}M) participants (p = 0.50). Q was not detected in human plasma. This validated method can now be used to further our understanding of the role of q/Q in nutrition, physiology and pathology.

biochemistry↗

bioRxiv2024

EpiCHAOS: a metric to quantify epigenomic heterogeneity in single-cell data

Epigenetic heterogeneity is a fundamental property of biological systems, and is recognized as a potential driver of tumor plasticity and therapy resistance. Single-cell epigenomics technologies have been widely employed to study epigenetic variation between - but not within - cellular clusters. We introduce epiCHAOS: a quantitative metric of cell-to-cell heterogeneity, applicable to any single-cell epigenomics data type. After validation in synthetic datasets, we applied epiCHAOS to investigate global and region-specific patterns of epigenetic heterogeneity across diverse biological systems. EpiCHAOS provides an excellent approximation of stemness and plasticity in development and malignancy, making it a valuable addition to single-cell cancer epigenomics analyses.

bioinformatics↗

bioRxiv2024

Figeno: multi-region genomic figures with long-read support

SummaryThe vast amount of publicly available genomic data requires analysis and visualization tools. Here, we present figeno, an application for generating publication-quality FIgures for GENOmics. Figeno particularly focuses on multi-region views across genomic breakpoints and on long reads with base modifications. Additionally, we support epigenomic data including ATAC-seq, ChIP-seq or HiC, as well as whole genome sequencing data with copy numbers and structural variants. Availability and ImplementationFigeno is available as a python package with both a command line and graphical user interface. It can be installed via PyPI and the source code is available at https://github.com/CompEpigen/figeno. Supplementary informationSupplementary data is provided.

bioinformatics↗

bioRxiv2024

Somatic epimutations enable single-cell lineage tracing in native hematopoiesis across the murine and human lifespan

Current approaches to lineage tracing of stem cell clones require genetic engineering or rely on sparse somatic DNA variants, which are difficult to capture at single-cell resolution. Here, we show that targeted single-cell measurements of DNA methylation at single-CpG resolution deliver joint information about cellular differentiation state and clonal identities. We develop EPI-clone, a droplet-based method for transgene-free lineage tracing, and apply it to study hematopoiesis, capturing hundreds of clonal trajectories across almost 100,000 single-cells. Using ground-truth genetic barcodes, we demonstrate that EPI-clone accurately identifies clonal lineages throughout hematopoietic differentiation. Applied to unperturbed hematopoiesis, we describe an overall decline of clonal complexity during murine ageing and the expansion of rare low-output stem cell clones. In aged human donors, we identified expanded hematopoietic clones with and without genetic lesions, and various degrees of clonal complexity. Taken together, EPI-clone enables accurate and transgene-free single-cell lineage tracing at scale.

genomics↗

bioRxiv2024

Functional analysis of the epilepsy gene Pcdh19 using a novel GFP-reporter mouse model

PCDH19 is a cell adhesion molecule belonging to the delta2-protocadherin subfamily that plays a critical role in brain development, neuronal migration, synaptic organisation, and neural circuit formation. Mutations in PCDH19 cause PCDH19-clustering epilepsy, an infantile-onset disorder characterized by seizures and intellectual disabilities. Despite the increasing development of constitutive cellular and murine models to investigate the effects of Pcdh19 knockout on cell-cell interactions and cellular function, the spatiotemporal consequences of its loss remain poorly understood. To address this gap, we generated and validated a novel conditional Pcdh19 knockout mouse model incorporating a GFP reporter (Pcdh19-cKO-GFP), enabling cell type-specific and temporally controlled gene deletion and direct visualization of recombination events. Using a neuronal Syn1-Cre driver, we demonstrate that targeted deletion of Pcdh19 in neurons results in altered hippocampal neurogenesis and mouse behaviour. We further demonstrate the versatility of this model using a doxycycline-inducible Cre system, enabling temporally controlled deletion of Pcdh19 and the modelling of disease-relevant phenotypes. Finally, we validate adeno-associated viral (AAV) vector-mediated recombination as a strategy for precise postnatal manipulation of Pcdh19 expression. Collectively, this Pcdh19-cKO-GFP model provides a powerful and flexible genetic tool to interrogate the cell type specific and temporary regulated functions of PCDH19 in the developing and postnatal brain under physiological and disease conditions.

neuroscience↗

bioRxiv2022

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

Inter-patient variability and the similarity of healthy and leukemic stem cells have impeded the characterization of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. While residual healthy cells dominated the dormant stem cell compartment, active leukemic stem cells resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors were highly aberrant and constituted the disease-defining compartment: Their gene expression and differentiation state determined both chemotherapy response and the leukemias ability to differentiate to transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers mis-regulated specifically in leukemic cells by intra-patient comparisons. Taken together, CloneTracer revealed a differentiation landscape that mimics its healthy counterpart and determines biology and therapy response in AML.

cancer biology↗