Biology subjects

Ho, C.

Publications and source records attributed to Ho, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx

The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.

bioengineering↗

bioRxiv2026

Toward routine health phenotyping: High-throughput prediction of metabolic, immune, and inflammatory biomarkers from milk mid-infrared spectroscopy in early-lactation dairy cows

This study evaluated the potential of milk mid-infrared (MIR) spectroscopy, combined with routinely available on-farm variables, for predicting serum metabolic, immune, and inflammatory biomarkers in early-lactation cows. Data included 5,936 blood samples from 4,442 cows across 23 Australian dairy herds, with paired milk MIR spectra and serum measurements for up to 14 biomarkers. Prediction models were developed using partial least squares regression and evaluated using nested 10-fold random cross-validation and leave-one-herd-out validation. The results show that while basic herd-test data, including milk fat, protein, and lactose concentration, as well as on-farm variables, including DIM, calving age, breed, and herd could predict serum biomarkers, combining MIR spectra with these on-farm variables produced the best overall performance. In random cross-validation, blood urea nitrogen (BUN) was predicted most accurately (R2 = 0.78), while {beta}-hydroxybutyrate (BHB) and nonesterified fatty acids (NEFA) showed moderate accuracy (R2 = 0.56 and 0.44, respectively). BUN also showed the strongest external validation performance, with leave-one-herd-out R2 = 0.58 and comparable accuracy for predicting records collected after 70 days in milk (R2 = 0.65). BHB and NEFA had moderate leave-one-herd-out accuracy but did not transfer beyond early lactation. Most other biomarkers showed low or inconsistent external validation performance. Overall, MIR spectroscopy combined with on-farm variables shows promise for routine prediction of BUN, BHB and NEFA, which can be used for monitoring and genetic evaluation of, for example, ketosis and energy deficit. Initial random cross-validation results for glucose, bilirubin and cholesterol were promising, but more data is needed to improve the prediction accuracy and robustness of the predictions. HighlightsO_LIMilk MIR can predict several serum biomarkers in early-lactation dairy cows. C_LIO_LIMIR-predicted blood urea nitrogen shows the greatest accuracy and robustness. C_LIO_LIMIR-predicted {beta}-hydroxybutyrate and nonesterified fatty acids show moderate accuracy. C_LIO_LIMost mineral, hepatic, and inflammatory biomarkers had limited accuracy. C_LIO_LIRoutine MIR phenotyping is most promising for BUN, BHB, and NEFA. C_LI SummaryMilk mid-infrared (MIR) spectroscopy and on-farm variables are evaluated as a high-throughput tool to predict health-related serum biomarkers in early-lactation dairy cows. The data include 5,936 paired blood and milk samples from 4,442 cows across 23 Australian dairy herds and up to 14 serum biomarkers. Prediction models are developed using partial least squares regression with nested random cross-validation and leave-one-herd-out validation. Blood urea nitrogen (BUN) shows the greatest and most transferable prediction accuracy across herds and lactation stages. {beta}-hydroxybutyrate (BHB) and nonesterified fatty acids (NEFA) are predicted with moderate accuracy, but only during early lactation. Random cross-validation results for glucose and bilirubin are promising, but larger datasets are needed for robust external validation. Most other mineral, hepatic, and inflammatory biomarkers show limited external prediction accuracy. These results indicate that MIR-based routine health phenotyping is most promising for BUN, BHB, and NEFA.

genetics↗

bioRxiv2026

Co-targeting Metabolic Neighbours Constraints Bacterial Adaptive Evolution

Antibiotic resistance often arises through genetic changes that reduce drug susceptibility, with mutation representing one of the primary mechanisms. Here, we report a dual targeting strategy that restricts these escape routes by simultaneously inhibiting two metabolic neighbours in folate biosynthesis pathway. To establish a general framework for limiting adaptive escape in bacteria, we screened the folate pathway to identify enzymes with shared conserved structural features. This analysis identified dihydroneopterin aldolase (folB) and dihydroneopterin triphosphate 2'-epimerase (folX) as optimal dual targets due to their shared pocket architecture and their roles early in the folate pathway. We then screened a large chemical space of FDA-approved small molecules to identify candidates predicted to bind both folB and folX, followed by experimental validation. We identified Arbutin showing the strongest growth inhibition in E. coli and emerging as the potent dual-target inhibitor, validated by metabolic rescue assays that confirmed direct inhibition of both folB and folX. Experimental evolution further revealed that populations exposed to Arbutin exhibit constrained adaptive trajectories and minimal increases in tolerated drug concentration, consistent with the evolutionary bottleneck imposed by dual-enzyme inhibition. Together, these results establish a framework for developing evolution-resistant antibacterials by targeting structurally convergent enzymes within metabolic pathways.

biophysics↗

bioRxiv2026

Host recovery after skin barrier disruption is individual-specific and associated with microbial functions

The human skin is repeatedly exposed to mechanical and environmental stress, particularly in common skin diseases such as eczema, and yet the determinants of recovery remain poorly understood. Using longitudinal, multimodal profiling of skin physiology, structure (Raman spectroscopy), and microbial communities (shotgun metagenomics), we investigated in a human cohort (n=36 subjects, x2 sites, x6 timepoints) how host-microbe interactions could jointly shape recovery. Despite baseline variability in physiological parameters, we established that our protocol enables a defined disruption of the stratum corneum. While recovery trajectories for host attributes were notably consistent across age groups and body sites, individual-specific differences in recovery timelines were observed. To assess the role of the skin microbiome, several key time-dependent changes in microbial species were identified including enrichment of select Cutibacterium and Staphylococcus species and depletion of Corynebacterium and Malassezia species. Clustering of microbiome stability profiles across subjects and sites identified 6 distinct groups which associate with varying host-recovery patterns and microbial functions. Finally, joint hazards modelling of recovery timing revealed significant contributions from microbial taxa, functions and stability groups, highlighting the under-appreciated role of host-microbial interactions in response to skin stress and in the recovery process.

genomics↗

bioRxiv2026

Objective Quality Assessment for Precision Functional MRI Data

Precision functional mapping (PFM) enables individual-level characterization of brain network organization but requires substantially more and higher-quality fMRI data than is standard. Despite its growing use, objective criteria for data sufficiency and quality needed to ensure interpretable and replicable individual-level results remain unclear. Here, we introduce the Network Similarity Index (NSI), an objective measure of the extent to which functional connectivity (FC) patterns in an individual dataset express the large-scale network structure required for PFM. NSI captures the integrity of low-spatial-frequency, coherent network organization and denoising fidelity, and aligns closely with blinded expert assessments of PFM usability. NSI also accounts for variability in the rate at which FC becomes reliable across individuals. Here, we provide an open-source framework for NSI-based data quality evaluation and models for linking NSI values with expert-judged PFM suitability. This framework can also inform expected returns from additional data collection, enabling principled decisions about data sufficiency and replication in precision fMRI research.

neuroscience↗

bioRxiv2025

Bruch's Membrane Contributes to the Structural Integrity of the Human Eye

PurposeTo investigate the contribution of the Bruchs membrane and sclera tissues to the overall structural integrity of the ocular wall. MethodsTwenty-three human globes were subjected to biomechanical testing. A piece of sclera measuring 5 x 5 mm was carefully removed at the nasal region, 2 mm away from the optic nerve head. The intraocular pressure was increased at approximately 1 mmHg/s until Bruchs membrane-uvea-retina-tissue layer (BMUR) ruptured. Next, strips of sclera and Bruchs membrane-choriocapillaris (BMC) complex were isolated from the superior fundus region. Uniaxial tension tests were performed at a strain rate of 0.01/s and sampling rate of 15 Hz. The tangent moduli of the BMC and sclera at 0.01, 0.02 and 0.03 strains were compared. ResultsThe rupture pressure of the BMUR was 98.1 {+/-} 21.4 mmHg. The tangent moduli of the BMC at 0.01, 0.02 and 0.03 strains were 2.96 {+/-} 1.44 MPa, 7.68 {+/-} 1.78 MPa and 9.43 {+/-} 2.11 MPa, respectively, and the tangent moduli of the sclera at 0.01, 0.02 and 0.03 strains were 1.09 {+/-} 0.80 MPa, 2.72 {+/-} 1.67 MPa and 5.69 {+/-} 3.27 MPa, respectively. ConclusionThe BMUR was able to sustain relatively high IOP before rupturing. The uniaxial tensile tests showed that the BMC tangent moduli were about 3 times of those of the sclera at strains of 0.01 and 0.02. Although the sclera is approximately 47 times thicker, the BMC is still likely to make a significant contribution (3.51% to 7.42% at strain <0.03) to the overall structural strength of the ocular wall.

bioengineering↗

bioRxiv2025

Thick filament molecular interfaces play a critical role in pathogenesis of hypertrophic and dilated cardiomyopathy

Hypertrophic (HCM) and dilated (DCM) cardiomyopathy variants in genes encoding the myosin heavy chain (MYH7), myosin light chains (MYL2 and MYL3), and cardiac myosin binding protein-C (cMyBP-C, MYBPC3) lead to cardiac hypertrophy or dilatation, with abnormal contractility, relaxation, and energy consumption. Here we defined the structural consequences of >200 pathogenic and benign missense variants in these genes by mapping variants onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 31 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the myosin heavy chain, essential and regulatory light chains, and cMyBP-C. Pathogenic DCM missense variants are rare, and altered only interfaces involving the myosin IHM and tails. None of the 21 variants classified as benign were within interfaces. We demonstrate earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within versus outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients. The dissimilar distribution of DCM and HCM variants could explain the different features of the two phenotypes.

biophysics↗

bioRxiv2025

Autonomous Reef Monitoring Structures (ARMS) Reveal Human-Induced Biodiversity Shifts in Urban Coastal Ecosystems

Biodiversity thrives in coastal marine habitats which host foundational species such as corals, mangroves, and seagrasses. However, coastal development and the growth of megacities along shorelines impose an array of stressors on the marine environment. These stressors inevitably impact biodiversity which dictates ecosystem functions and services. Despite extensive research on biodiversity responses to anthropogenic stressors, phylum-specific resistance and resilience dynamics - particularly in coastal marine ecosystems - remain poorly understood. Considering the global scale of coastal development, it is imperative to develop a more comprehensive understanding of how biodiversity, in terms of richness and community composition, is influenced by various anthropogenic stressors. Here, we present the first application of standardized Autonomous Reef Monitoring Structures (ARMS) as an experimental unit - using a common garden experimental design - to examine community responses to stress within an urbanized seascape. ARMS were seeded within two marine reserves for one year and then transplanted to sites of stress, including domestic sewage, and mariculture. We hypothesized that 1) human impacts reduce richness and alter composition of established communities; and 2) increasing intensity of these impacts reduces community resistance and resilience to stress. Using metabarcoding, we quantified richness and taxonomic composition and assessed their changes along an impact gradient. Our results showed that nutrient pollution, particularly inorganic nitrogen, significantly reduced species richness and restructured communities. Communities exhibited low resistance, yet high resilience - suggesting that urbanized seascapes have high recovery potential when stress is mitigated.

ecology↗

bioRxiv2025

Derivation of cardiomyocyte-propelled motile aggregates from stem cells

Robotics draws inspiration from biology, particularly animal locomotion based on muscle-driven contractions. While traditional engineering assembles components sequentially, locomotive animals are built via self-organized developmental programs. Stem cells, under the right conditions, can mimic these processes in vitro, offering a pathway to develop muscle-propelled biobots in a self-organized building process. Here, we demonstrate that existent cardiogenic gastruloid protocols can produce motile aggregates from mouse embryonic stem cells, although with very limited efficiency. We then identify a novel protocol that yields contractile aggregates with higher frequency and larger contractile areas. In this novel protocol, mesendoderm induction using TGF-beta ligands is followed by cardiogenic induction with FGFs and VEGF. Synthetic organizers further control contraction localization. Aggregates developed via this protocol show enhanced motility, marking a step forward towards building motile cardiobots from self-organized biological material. This strategy opens new possibilities for designing autonomous biobots and studying the evolution of muscle-powered movement of multicellular organisms and cardiovascular development.

synthetic biology↗

bioRxiv2025

A wireless, 60-channel, AI-enabled neurostimulation platform

ObjectiveClosed-loop neuromodulatory therapies require devices that can both decode ongoing brain states and deliver multi-site stimulation. MethodsWe describe the Smart Neurostimulation System (SNS), a cranially mounted implant with 60 configurable recording/stimulation channels, inductive power, and onboard spectral-feature classification. In three freely-moving sheep we streamed local-field potentials and conducted two parameter sweep experiments. ResultsCross-validated movement classifiers achieved an average AUC > 0.95. Increasing stimulation amplitude and frequency produced post-stimulation elevations in -band (8-12 Hz) and{gamma} -band (78-82 Hz) power at most target locations. ConclusionThe SNS unifies high-density sensing, real-time brain state decoding, and programmable closed-loop stimulation in a single device, demonstrating behavioral-state prediction and parameter-dependent neuromodulation in vivo. SignificanceThese findings establish a preclinical foundation for biomarker-guided stimulation targeting distributed cortical networks underlying memory and cognition. HighlightsO_LIWireless 60-channel implant enables simultaneous sensing and stimulation C_LIO_LIvine study demonstrates reliable classification of movement and stimulation-related modulation of spectral activity C_LIO_LIThe SNS represents a platform for biomarker-guided neuromodulation therapies C_LI

neuroscience↗

bioRxiv2024

Chemically-inducible CRISPR/Cas9 circuits for ultra-high dynamic range gene perturbation

CRISPR/Cas9 technologies provide unique capabilities for modeling disease and understanding gene-to-phenotype connections. In cultured cells, chemical-mediated control of Cas9 activity can limit off-target effects and enable mechanistic study of essential genes. However, widely-used Tet-On systems often show "leaky" Cas9 expression, leading to unintended edits, as well as weak activity upon induction. Leakiness can be distinctly problematic in the context of Cas9 nuclease activity, which may result in cumulative DNA damage and degradation of the target cell genome over time. To overcome these deficiencies, we established transgenic platforms that minimize Cas9 functionality in the off-state along with maximized and uncompromised on-state gene editing efficiency. By combining conditional destabilization and inhibition of Cas9, we developed an all-in-one (one or multiple guide RNAs and Cas9) ultra-tight, Tet-inducible system with exceptional dynamic range (on vs. off-state) across various cell lines and targets. As an alternative to Tet-mediated induction, we created a branaplam-regulated splice switch module for low-baseline and robust Cas9 activity control. Lastly, for circumstances where DNA damage needs to be avoided, we constructed a dual-control, Tet-inducible CRISPRi module for tight and potent transcriptional silencing. This upgraded suite of inducible CRISPR systems has broad applications for numerous cell types and experimental conditions.

molecular biology↗

bioRxiv2024

The Senescence-Associated-Secretory Phenotype constituting HIF-1α activation is independent of micronuclei induction and associated cGAS-mediated interferon response

The Senescence-Associated Secretory Phenotype (SASP), characterized by the upregulation of inflammatory cytokines, is triggered during senescence by anti-proliferation stresses, including replicative exhaustion, {gamma}-irradiation, Ras oncogene induction, and centrosome amplification. The elucidation of common signalling pathway(s) activated in SASP, induced by different anti-proliferation stresses, remains an important question. Indeed, micronuclei activation of the cGAS/Sting pathway, which has been thought to drive SASP(Kwon, Leibowitz, and Lee, 2020), remains controversial(Flynn, Koch, and Mitchison, 2021; Sato and Hayashi, 2024; Takaki et al., 2024). In this report, analyses of various cell lines induced to undergo senescence by diverse stressors revealed that HIF-1 is specifically induced in senescence but not in quiescence. Consistent with our previous findings(Wu et al., 2023a), we have further demonstrated how centrosome amplification induces a non-canonical SASP dominated by HIF-1 activation rather than the classical NF{kappa}B signaling. Lastly, we revealed that during SASP, centrosome amplification-generated micronuclei do not activate the cGAS/Sting-mediated interferon response. Together, our findings demonstrate that HIF-1-activation in SASP is a defining feature of the SASP induced by diverse stressors, acting independently of micronuclei generation and cGAS/Sting activation.

cell biology↗

bioRxiv2024

Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

AbstractO_ST_ABSIntroductionC_ST_ABSAlzheimers disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. MethodsDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). ResultsAs a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. DiscussionThis comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

neuroscience↗

bioRxiv2024

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations

INTRODUCTIONMulti-omics studies in Alzheimers disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODSTo bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTSWe generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSIONInclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

neuroscience↗

bioRxiv2024

Nonreciprocal synchronization in embryonic oscillator ensembles

Synchronization of coupled oscillators is a universal phenomenon encountered across different scales and contexts e.g., chemical wave patterns, superconductors and the unison applause we witness in concert halls. The existence of common underlying coupling rules define universality classes, revealing a fundamental sameness between seemingly distinct systems. Identifying rules of synchronization in any particular setting is hence of paramount relevance. Here, we address the coupling rules within an embryonic oscillator ensemble linked to vertebrate embryo body axis segmentation. In vertebrates, the periodic segmentation of the body axis involves synchronized signaling oscillations in cells within the presomitic mesoderm (PSM), from which somites, the pre-vertebrae, form. At the molecular level, it is known that intact Notch-signaling and cell-to-cell contact is required for synchronization between PSM cells. However, an understanding of the coupling rules is still lacking. To identify these, we develop a novel experimental assay that enables direct quantification of synchronization dynamics within mixtures of oscillating cell ensembles, for which the initial input frequency and phase distribution are known. Our results reveal a "winner-takes-it-all" synchronization outcome i.e., the emerging collective rhythm matches one of the input rhythms. Using a combination of theory and experimental validation, we develop a new coupling model, the "Rectified Kuramoto" (ReKu) model, characterized by a phase-dependent, non-reciprocal interaction in the coupling of oscillatory cells. Such non-reciprocal synchronization rules reveal fundamental similarities between embryonic oscillators and a class of collective behaviours seen in neurons and fireflies, where higher level computations are performed and linked to non-reciprocal synchronization.

systems biology↗

bioRxiv2023

Characterization and diversification of AraC/XylS family regulators guided by transposon sequencing

In this study, we explored the development of engineered inducible systems. Publicly available data from previous transposon sequencing assays were used to identify regulators of metabolism in Pseudomonas putida KT2440. For the AraC-family regulators (AFRs) represented in this data, we posited AFR/promoter/inducer groupings. Eleven promoters were characterized for a response to their proposed inducers in P. putida, and the resultant data were used to create and test nine two-plasmid sensor systems in E. coli. Several of these were further developed into a palette of single-plasmid inducible systems. From these experiments, we observed an unreported inducer response from a previously characterized AFR, demonstrated that the addition of a P. putida transporter improved the sensor dynamics of an AFR in E. coli, and identified an uncharacterized AFR with a novel potential inducer specificity. Finally, targeted mutations in an AFR, informed by structural predictions, enabled further diversification of these inducible plasmids. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/550116v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@fb1ee2org.highwire.dtl.DTLVardef@a88f1dorg.highwire.dtl.DTLVardef@4bbd5borg.highwire.dtl.DTLVardef@7cdbfc_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2023

The pGinger family of expression plasmids

The pGinger suite of expression plasmids comprises 43 plasmids that will enable precise constitutive and inducible gene expression in a wide range of gram-negative bacterial species. Constitutive vectors are composed of 16 synthetic constitutive promoters upstream of RFP, with a broad host range BBR1 origin and a kanamycin resistance marker. The family also has seven inducible systems (Jungle Express, Psal/NahR, Pm/XylS, Prha/RhaS, LacO1/LacI, LacUV5/LacI, and Ptet/TetR) controlling RFP expression on BBR1/kanamycin plasmid backbones. For four of these inducible systems (Jungle Express, Psal/NahR, LacO1/LacI, and Ptet/TetR), we created variants that utilize the RK2 origin and spectinomycin or gentamicin selection. Relevant RFP expression and growth data have been collected in the model bacterium Escherichia coli as well as Pseudomonas putida. All pGinger vectors are available via the Joint BioEnergy Institute (JBEI) Public Registry.

synthetic biology↗

bioRxiv2022

Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms1, 2. Pre-leukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies3-5, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures6-12 from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as a temporal barcode in each patients life, we estimate that several complex events and genomic drivers are acquired after chemotherapy exposure. In the case of treatment with high-dose melphalan and autologous stem cell transplantation, we demonstrate that the procedure allows clonal hematopoiesis to escape chemotherapy exposure entirely, and to be reinfused to expand to malignancy. This information reveals a novel mode of malignant progression for therapy-related malignancies that is not reliant on direct mutagenesis or even exposure to chemotherapy, itself, and prompts further investigation into leukemia-permissive effects of cytotoxic drugs.

cancer biology↗