Biology subjects

Xue, Y.

Publications and source records attributed to Xue, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Cell Type Specific Responses of the Endoplasmic Reticulum Dynamics to Environmental Stress

To overcome the challenge of balancing imaging speecd and resolution, which currently limits the accurate identification of structural and dynamic changes in the study of endoplasmic reticulum (ER) in plant cells. This research employs structured illumination microscopy techniques to achieve super-resolution real-time imaging of the ER in live Arabidopsis materials. Additionally, a self-supervised denoising framework (Blind2Unblind) was optimized to further enhance the signal-to-noise ratio of rapid microscopic imaging. Based on the images with high quality, a method for quantitative analysis of ER structures using time-lapse images is developed. Moreover, detections of changes in ER structures under environmental stress are conducted to verify the effectiveness of the method. Moreover, correlation analyses of various parameters indicate a significant positive correlation between the area and length of tubular ER with the number of growth tips and tricellular junctions, while the area of ER cisternae and bulk flow exhibits a significant negative correlation with the area and length of tubules. The super-resolution imaging and dynamic analysis method developed in this study will provide new technical approaches for further elucidating the function and regulatory mechanisms of the plant ER.

plant biology↗

bioRxiv2023

Chlamydial protease-like activating factor targets SLC7A11 for degradation to induce ferroptosis and facilitate dissemination.

Chlamydia trachomatis, the most prevalent bacterial agent of sexually transmitted infections, possesses remarkable capacities for dissemination within the host, leading to reproductive health complications. The release of progeny through the orchestrated lysis of host cells plays a crucial role in Chlamydia dissemination, but the underlying molecular mechanisms remain largely elusive. Here, we uncovered a novel mechanism by which Chlamydia induces host cells ferroptosis to facilitate its dissemination. This process involves the degradation of host protein SLC7A11 by the chlamydial protease-like activating factor (CPAF), resulting in glutathione depletion, oxidative damage, and subsequent host cell lysis characterized by lipid peroxidation. Infection with CPAF-deficient strain fails to induce host cells ferroptosis, leading to restricted progeny release. Importantly, inhibiting ferroptosis effectively limits the release of Chlamydia progeny, highlighting its potential as a therapeutic strategy for controlling Chlamydia dissemination. These findings provide insights into the chlamydial conserved dissemination strategy and enhance understanding of its pathogenesis.

microbiology↗

bioRxiv2023

pan-MHC and cross-Species Prediction of T Cell Receptor-Antigen Binding

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of {beta} T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.

immunology↗

bioRxiv2023

A genome-wide association study of neonatal metabolites

The hereditary component significantly influences the concentration of metabolites in adults. Nevertheless, the precise influence of genetic factors on neonatal metabolites remains uncertain. To bridge this gap, we employed genotype imputation techniques on large-scale low-pass genome data obtained from non-invasive prenatal testing. Subsequently, we conducted association studies on a total of 75 metabolic components in neonates. The study identified a total 17 previous reported associations and 13 novel discovered associations between single nucleotide polymorphisms and metabolic components. These associations were initially found in the discovery cohort (8,744 participants) and subsequently confirmed in a replication cohort (19,041 participants). The average heritability of metabolic components was calculated to be 76.2%, with a range of 69-78.8%. The aforementioned findings offer valuable insights pertaining to the genetic architecture of neonatal metabolism. In BriefLarge-scale genomes of maternal non-invasive prenatal testing provide insights into the genetic contribution to neonatal metabolism. HighlightsGWAS of 27,785 low-pass genomes revealed 13 novel associations of neonatal metabolic components. Estimated an average of 76.2% heritability of neonatal metabolic components and showed the individual concentration can be accurately predicted from polygenic risk scores. A total of 17 established relationships have been observed, providing evidence that maternal genomes can be utilized in neonatal metabolite GWAS.

genetics↗

bioRxiv2023

Comparing virtual staining artificial intelligence model performance on same-tissue versus serial-tissue sections based on CD3+ T-cell ground truth

Immunophenotyping via multi-marker assays significantly contributes to patient selection, therapeutic monitoring, biomarker discovery, and personalized treatments. Despite its potential, the multiplex immunofluorescence (mIF) technique faces adoption challenges due to technical and financial constraints. Alternatively, hematoxylin and eosin (H&E)-based prediction models of cell phenotypes can provide crucial insights into tumor-immune cell interactions and advance immunotherapy. Current methods mostly rely on manually annotated cell label ground truths, with limitations including high variability and substantial labor costs. To mitigate these issues, researchers are increasingly turning to digitized cell-level data for accurate in-situ cell type prediction. Typically, immunohistochemical (IHC) staining is applied to a tissue section serial to one stained with H&E. However, this method may introduce distortions and tissue section shifts, challenging the assumption of consistent cellular locations. Conversely, mIF overcomes these limitations by allowing for mIF and H&E staining on the same tissue section. Importantly, the multiplexing capability of mIF allows for a thorough analysis of the tumor microenvironment by quantifying multiple cell markers within the same tissue section. In this study, we introduce a Pix2Pix generative adversarial network (P2P-GAN)-based virtual staining model, using CD3+ T-cells in lung cancer as a proof-of-concept. Using an independent CD3 IHC-stained lung cohort, we demonstrate that the model trained with cell label ground-truth from the same tissue section as H&E staining performed significantly better in both CD3+ and CD3- T-cell prediction. Moreover, the model also displayed prognostic significance on a public lung cohort, demonstrating its potential clinical utility. Notably, our proposed P2P-GAN virtual staining model facilitates image-to-image translation, enabling further spatial analysis of the predicted immune cells, deepening our understanding of tumor-immune interactions, and propelling advancements in personalized immunotherapy. This concept holds potential for the prediction of other cell phenotypes, including CD4+, CD8+, and CD20+ cells.

immunology↗

bioRxiv2023

High temporal frequency light response in mouse retina is mediated by ON and OFF bipolar cells and requires FAT3 signaling

Vision is initiated by the reception of light by photoreceptors and subsequent processing via downstream retinal neurons. Proper cellular organization depends on the multi-functional tissue polarity protein FAT3, which is required for amacrine cell connectivity and retinal lamination. Here we investigated the retinal function of Fat3 mutant mice and found decreases in physiological and perceptual responses to high frequency flashes. These defects did not correlate with abnormal amacrine cell wiring, pointing instead to a role in bipolar cell subtypes that also express FAT3. The role of FAT3 in the response to high temporal frequency flashes depends upon its ability to transduce an intracellular signal. Mechanistically, FAT3 binds to the synaptic protein PTP{sigma}, intracellularly, and is required to localize GRIK1 to OFF-cone bipolar cell synapses with cone photoreceptors. These findings expand the repertoire of FAT3s functions and reveal its importance in bipolar cells for high frequency light response.

neuroscience↗

bioRxiv2023

G protein subunit Gγ13-mediated signaling pathway is critical to the inflammation resolution and functional recovery of severely injured lungs

Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit G{gamma}13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the G{gamma}13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.

immunology↗

bioRxiv2023

Single-cell mitochondrial variant enrichment resolved clonal tracking and spatial architecture in human embryonic hematopoiesis

The ability to perform lineage tracing at the single-cell level is critical to reconstructing dynamic transitions during cell differentiation. However, prospective tracing approaches inevitably encounter outstanding challenges including barcoding precision, barcode diversity, and detection efficiency, which can skew inferred lineage relationships. Human pluripotent stem cells (hPSCs) even face risks of DNA-damage-induced toxicity-related cell death. We explored the use of naturally occurring somatic mutations in mitochondrial transcripts detected in single-cell RNA-seq as genetic lineage barcodes in hPSCs. In this study, we used an enrichment of scRNA-seq mitochondrial reads and a robust computational method to identify clonally relevant mitochondrial variants as endogenous genetic barcodes for clonal tracking of early embryonic hematopoiesis from hPSC. We modeled the development of embryonic tissues from hPSCs and delineated cell fate specification by integrating synthetic barcoding with mitochondrial lineage tracing. Using a biophysical model, we reconstructed the sequential transcriptional logic of fate specification and its underlying regulatory network. We further applied mitochondrial lineage tracing to spatial transcriptomics, which enabled us to identify the spatial clonal architecture of human embryonic organoids. Our analysis revealed that this spatial zonation was orchestrated by NOTCH-mediated crosstalk between stromal cells and hematopoietic progenitors. Our multi-modal framework links clonal dynamics with niche-specific fate decisions, providing a generalizable approach to dissecting tissue organization in development and disease. This study underscores the utility of mitochondrial variants as endogenous markers for high-resolution spatial clonal tracking in stem cell-derived organoid models of human development.

developmental biology↗

bioRxiv2023

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

KRASG12C inhibitors including adagrasib and sortorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurring KRASG12C and STK11/LKB1 mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies of Lkb1-deficient KRASG12Cand KrasG12D lung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed {Delta}Np63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked by Krt6a upregulation. Notably, higher KRT6A expression at baseline correlated with shorter overall survival in KRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.

cancer biology↗

bioRxiv2023

Phase separation of S-RNase promotes self-incompatibility in Petunia hybrida

SummarySelf-incompatibility (SI) is an intraspecific reproductive barrier widely present in angiosperms. The SI system with the broadest occurrence in angiosperms is based on an S-RNase linked to a cluster of multiple S-locus F-box (SLF) genes found in the Solanaceae, Plantaginaceae, Rosaceae, and Rutaceae. Recent studies reveal that non-self S-RNase is degraded by the SCFSLF-mediated ubiquitin-proteasome system in a collaborative manner in Petunia, but how self-RNase functions largely remains mysterious. Here, we show that S-RNases form S-RNase condensates (SRCs) in the self-pollen tube cytoplasm through phase separation and their disruption breaks SI in self-incompatible Petunia hybrida. We further find that the pistil SI factors of a small asparagine-rich protein HT-B and thioredoxin h (Trxh) together with a reduced state of the pollen tube all promote the expansion of SRCs, which then sequester several actin binding proteins, including the actin polymerization factor PhABRACL, whose actin polymerization activity is reduced by S-RNase in vitro. Meanwhile, we find that S-RNase variants lacking condensation ability fail to recruit PhABRACL and are unable to induce actin foci formation required for the pollen tube growth inhibition. Taken together, our results demonstrate that phase separation of S- RNase promotes SI response in P. hybrida, revealing a new mode of S-RNase action.

genetics↗

bioRxiv2023

SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression

The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis. SignificanceSince its emergence in 2019, SARS-CoV-2 has accrued mutations throughout its 30kb genome. Of particular interest are the mutations present in the ORF8 protein, which occur in every major variant. The precise function and impact of this protein on disease severity and pathogenesis remains understudies. Our studies reveal that the ORF8 protein modulates the immune response by impacting macrophage infiltration into the lungs. Additionally, we have shown that the ORF8 protein of SARS-CoV-2 has accrued mutations throughout its evolution that lead to a loss of function phenotype in this protein. Our work reveals that the ORF8 protein of SARS-CoV-2 contributes significantly to disease progression through modulation of the inflammatory response.

microbiology↗

bioRxiv2023

Different coexistence patterns between apex carnivores and mesocarnivores based on temporal, spatial, and dietary niche partitioning analysis in Qilian Mountain National Park, China

Carnivores play key roles in maintaining ecosystem structure and function as well as ecological processes. Understanding how sympatric species coexist in natural ecosystems is a central research topic in community ecology and biodiversity conservation. In this study, we explored intra- and interspecific niche partitioning along spatial, temporal, and dietary niche partitioning between apex carnivores (wolf Canis lupus, snow leopard Panthera uncia, Eurasian lynx Lynx lynx) and mesocarnivores (Pallass cat Otocolobus manul, red fox Vulpes vulpes, Tibetan fox Vulpes ferrilata) in Qilian Mountain National Park, China using camera trapping data and DNA metabarcoding sequencing data. Our study showed that apex carnivore species had more overlap temporally (coefficients of interspecific overlap ranging from 0.661 to 0.900) or trophically (Piankas index ranging from 0.458 to 0.892), mesocarnivore species had high dietary overlap with each other (Piankas index ranging from 0.945 to 0.997), and apex carnivore and mesocarnivore species had high temporal overlap (coefficients of interspecific overlap ranging from 0.497 to 0.855). Large dietary overlap was observed between wolf and snow leopard (Piankas index=0.892) and Pallass cat and Tibetan fox (Piankas index=0.997), suggesting the potential for increased resource competition for these species pairs. We concluded that spatial niche partitioning is likely to key driver in facilitating the coexistence of apex carnivore species, while spatial and temporal niche partitioning likely facilitate the coexistence of mesocarnivore species, and spatial and dietary niche partitioning facilitate the coexistence between apex and mesocarnivore species. Our findings consider partitioning across temporal, spatial and dietary dimensions while examining diverse coexistence patterns of carnivore species in Qilian Mountain National Park, China. These findings will contribute substantially to current understanding of carnivore guilds and effective conservation management in fragile alpine ecosystems.

ecology↗

bioRxiv2023

Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model

Retinitis pigmentosa (RP) is a prevalent inherited retinal degenerative disease worldwide, affecting 1 in 4,000 people. The disease is characterized by an initial loss of night vision followed by a loss of daylight and color vision. Many of the RP disease genes are expressed in the rod photoreceptors, the cell type that initiates dim light vision. Following loss of rods, the cone photoreceptors, which initiate daylight vision, also are affected and can die leading to total loss of vision. The reasons for loss of cone vision are not entirely clear, but appear to be due to loss of the rods. Previously we showed that overexpressing Txnip, an -arrestin protein, in mouse models of RP using AAV gene therapy prolonged the survival of RP cones (Xue et al., 2021). At least part of the mechanism for cone survival was a switch in the fuel source, from glucose to lactate. In addition, the mitochondria of cones were both morphologically and functionally improved by delivery of Txnip. We have gone on to test several alleles of Txnip for the ability to prolong cone survival in rd1, a mouse model of RP. In addition, proteins that bind to Txnip and/or have homology to Txnip were tested. Five different deletion alleles of Txnip were expressed in cones or the retinal pigmented epithelium (RPE). Here we show that the C-terminal half of Txnip (149-397aa) is sufficient to remove GLUT1 from the RPE cell surface, and improved rd1 cone survival when expressed specifically in the RPE. Overexpressing Arrdc4, an -arrestin that shares 60% similar protein sequence to Txnip, reduced rd1 cone survival. Reduction of the expression of HSP90AB1, a protein that interacts with Txnip and regulates metabolism, improved the survival of rd1 cones alone and was additive for cone survival when combined with Txnip. However, full length Txnip with a single amino acid change, C247S, as we tested in our original study, remains the most highly efficacious form of the gene for cone rescue. The above observations suggest that only a subset of the hypothesized and known activities of Txnip play a role in promoting RP cone survival, and that the activities of Txnip in the RPE differ from those in cone photoreceptors.

physiology↗

bioRxiv2023

ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus

Katanin catalytic subunit A1 like 2 (KATNAL2) is a high-risk gene associated with autism spectrum disorders (ASD), however its impact on brain development and disease remains unclear. The present study revealed an unexpected role of KATNAL2 in regulating ependymal ciliary motion and cerebrospinal fluid flow during brain development, an important contributing factor for ASD. We discovered a distinct expression pattern of KATNAL2 in multiciliated ependymal cells of both human and mouse brains. Notably, an ASD-associated mutation of Katnal2 disrupted its molecular function and resulted in ASD-related behavioral deficits in mice. Additionally, this mutation affected the polarized organization and beating of ependymal cilia, leading to delayed cerebrospinal fluid flow and sustained ventricular enlargement from the early postnatal stage. Conditional ablation of Katnal2 specifically in the ependymal cells of neonatal mice is sufficient to cause ventricular dilation, whereas no such effect was observed in adult mice. Our findings highlight the importance of ependymal motile cilia and hydrocephalus in ASD, offering insights into its pathogenesis and potential intervention.

neuroscience↗

bioRxiv2023

Coordinated wound responses in a regenerative animal-algal photosymbiotic metaorganism

Animal regeneration requires coordinated responses of many cell types throughout the animal body. In animals carrying endosymbionts, cells from the other species may also participate in regeneration, but how cellular responses are integrated across species is yet to be unraveled. Here, we study the acoel Convolutriloba longifissura, which hosts symbiotic Tetraselmis green algae and can regenerate entire bodies from small tissue fragments. We show that animal injury leads to a decline in the photosynthetic efficiency of the symbiotic algae and concurrently induces upregulation of a cohort of photosynthesis-related genes. A deeply conserved animal transcription factor, runt, is induced after injury and required for the acoel regeneration. Knockdown of runt also dampens algal transcriptional responses to the host injury, particularly in photosynthesis related pathways, and results in further reduction of photosynthetic efficiency post-injury. Our results suggest that the runt-dependent animal regeneration program coordinates wound responses across the symbiotic partners and regulates photosynthetic carbon assimilation in this metaorganism.

developmental biology↗

bioRxiv2023

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. Short abstractIntrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

neuroscience↗

bioRxiv2023

Identification of immune-related genes for the diagnosis of ischaemic heart failure based on bioinformatics and three machine learning models

BackgroundThe role of immune cells in the pathogenesis of ischaemic heart failure (IHF) is well-established. However, identifying key diagnostic candidate genes in patients with IHF remains a challenge. Therefore, this study aimed to use bioinformatics and machine learning algorithms to identify potential diagnostic genes for IHF. MethodsTwo IHF datasets were obtained from the GEO database, and key genes for IHF were identified using Limma and WGCNA. Functional enrichment analysis was performed to explore the potential mechanisms of IHF. Next, we used three machine learning algorithms, namely LASSO, RF, and SVM-REF, to identify immune-related diagnostic genes for IHF. ssGSEA enrichment analysis was also completed. To assess the diagnostic value of the identified genes, we developed nomogram and validated them on additional GEO datasets. Finally, an immune infiltration analysis was conducted using the CIBERSORT algorithm to explore immune cell dysregulation in IHF. ResultsOur analysis yielded a total of 92 key genes associated with IHF. Enrichment analysis revealed that the mechanisms underlying IHF are mostly associated with immunity and inflammation. Using the machine learning algorithms, we identified four IHF diagnostic genes, namely RNASE2, MFAP4, CHRDL1, and KCNN3. We constructed nomogram and validated the diagnostic value of these genes on additional GEO datasets. The results showed that these four genes had high diagnostic value (AUC value of 0.961). Furthermore, our immune infiltration analysis revealed the presence of three dysregulated immune cells in IHF, namely Macrophages M2, Monocytes, and T cells gamma delta. ConclusionIn summary, our study identified four potential diagnostic candidate genes for IHF by using bioinformatics and machine learning algorithms. We also explored the potential molecular mechanisms of IHF and the immune cell infiltration environment of the failing myocardium. These findings provide new insights into the pathogenesis, diagnosis, and treatment of IHF.

bioinformatics↗

bioRxiv2023

Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification

Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.

cancer biology↗