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Liu, H.

Publications and source records attributed to Liu, H..

At least 379 records · Page 21Linked to original sources

Nearly complete genome assembly of a critically endangered pine illuminates evolution and conservation of conifers

Population genetic theory predicts that severe bottlenecks and extremely small effective population sizes (Ne) should reduce the ability of natural selection to eliminate harmful mutations. Under this framework, deleterious alleles are expected to accumulate and even fix, eroding fitness, constraining evolutionary rescue, and potentially precipitating mutational meltdown. Yet, empirical tests of these predictions in species at the extreme lower bound of Ne remain rare. We address this gap using Pinus squamata, one of the rarest tree species on Earth, with only 35 wild individuals remaining. We generated a near-complete reference genome (29.2 Gb) for this species and performed population genomic analyses across nearly all of its extant individuals, together with two closely related species. P. squamata exhibits extraordinarily low nucleotide diversity ({pi} = 3.35 x 10-), the lowest reported for any plant. Demographic inference reveals a recent and severe bottleneck ([~]20 generations ago) that reduced Ne to [~]2.7 and resulted in intense inbreeding. Contrary to theoretical expectations, we uncover evidence for highly efficient purifying selection: strongly deleterious mutations are markedly depleted, indicating substantial purging despite the extremely small Ne. Genome-wide patterns further implicate selection at linked sites--including background selection and pseudo-overdominance--as dominant forces shaping genomic variation in the species. These results challenge the prevailing view that drift overwhelms selection in extremely small populations. Instead, they suggest that, under certain genomic and demographic conditions, purifying selection can remain unexpectedly effective, potentially mitigating the risk of mutational meltdown in the rarest species.

genomics↗

A Small Interfering Peptide Potentiates AMPA Receptor Diffusional Trapping and Prevents Social-Isolation-Induced Forgetting of Fear Memory

Synaptic trapping of AMPA receptors (AMPARs) is a key mechanism regulating excitatory synaptic transmission and activity-dependent plasticity underlying learning and memory. Destabilization of synaptic AMPARs is increasingly implicated in cognitive dysfunction across neurological and neuropsychiatric disorders, yet strategies to directly modulate this process in vivo remain limited, constraining both mechanistic insight and therapeutic development. Here we present a peptide-based strategy to enhance AMPAR synaptic trapping by targeting the interaction between transmembrane AMPA receptor regulatory proteins (TARPs) and activity-regulated cytoskeleton-associated protein (ARC/Arg3.1). We designed a 21-amino-acid TAT-fused peptide (TARP-pep) mimicking the TARP C-terminal motif that binds the ARC N-lobe. TARP-pep disrupted the TARP-ARC interaction and increased the stabilization of AMPARs at synaptic surfaces in cultured hippocampal neurons. In vivo, acute intrahippocampal infusion of TARP-pep enhanced perforant path-evoked synaptic transmission in the rat dentate gyrus (DG) and strengthened the interaction between TARPs and postsynaptic density protein 95 (PSD-95), a key mechanism underlying AMPAR anchoring. Consistent with a long-term potentiation (LTP)-like synaptic state, TARP-pep increased basal phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and occluded further chemical LTP (cLTP)-induced increases in phosphorylated CaMKII (p-CaMKII). Notably, a 7-day regimen of daily bilateral DG injections of TARP-pep prevented social isolation (SI)-induced impairment of fear memory in mice. Together, these findings identify the TARP-ARC interaction as a druggable regulator of AMPAR diffusional trapping and highlight synaptic AMPAR stabilization as a promising therapeutic strategy for preserving cognitive function under conditions of circuit vulnerability.

neuroscience↗

CRISPR screens reveal ZBTB17/MIZ1 as a peroxisome regulator

Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes in humans, with defects often linked to diseases. The functions of peroxisomes are regulated at transcriptional, translational, and post-translational levels. In this study, we employed the CRISPR/Cas9-based genetic screening of a ubiquitin ligase library to identify regulators of human peroxisomes. We discovered that ZBTB17 (also referred as MIZ1) plays a role in regulating the import of proteins into peroxisomes. Independent of its ubiquitin ligase activity, ZBTB17/MIZ1 operates as a transcription factor to directly modulate the expression of key importer PEX13, thereby influencing the localization of peroxisomal enzymes. Furthermore, metabolomic profiling reveals that the knockdown of ZBTB17 or PEX13 results in similar metabolic alterations, characterized by downregulated purine synthesis, suggesting that ZBTB17s role in metabolic regulation likely operates through peroxisomes. Collectively, we identify ZBTB17 as a key regulator of peroxisomal protein import, thereby affecting peroxisomal function and nucleotide metabolism. Our findings provide insights into the multifaceted regulation of peroxisomes in complex human cells and shed light on the molecular mechanisms underlying ZBTB17s role as a transcriptional regulator.

cell biology↗

Expectation modulates learning emotional words: Evidence from a hierarchical Bayesian model

In language acquisition, individuals learn the emotional value of words through external feedback. Previous studies have used emotional words as experimental materials to explore the cognitive mechanism underlying emotional language processing, but have failed to recognize that languages are acquired in a changing environment. To this end, this study aims to combine reinforcement learning with emotional word learning, using a probabilistic reversal learning task to explore how individuals acquire the valence of emotional words in a dynamically changing environment. Our computational modeling on both behavioral and event-related potential (ERP) data revealed that individuals expectations can modulate the learning speed and temporal processing of emotional words, demonstrating a clear negative bias. Specifically, as the expected value increases, individuals respond faster and exhibit higher amplitudes for negative emotional words. These findings shed light on the neural mechanisms of emotional word learning in a volatile environment, highlighting the crucial role of expectations in this process and the preference for processing negative information.

neuroscience↗

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation

ObjectivesChondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development. MethodsHuman and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5-/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB). ResultsWe found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaKs predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes. ConclusionsWe found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.

cell biology↗

PA2gamma promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

Proteasome activator 28{gamma} (PA28{gamma}) plays a critical role in malignant progression of various tumors, however, its role and regulation are not well understood. Here, using oral squamous cell carcinoma (OSCC) as main research model, we discovered that PA28{gamma} interacted with complement 1q binding protein (C1QBP), which is dependent on the N-terminus of C1QBP rather than the known functional domain (amino acids 168-213). Notably, we found that PA28{gamma} enhances C1QBP protein stability in OSCC. Functionally, PA28{gamma} contributes to the malignant progression of OSCC by affecting mitochondrial morphology and oxidative phosphorylation (OXPHOS) through C1QBP in vitro and vivo. Mechanically, PA28{gamma} upregulates the expression of optic atrophy 1 (OPA1), mitofusin 1 (MFN1), mitofusin 2 (MFN2), and the mitochondrial respiratory complex via C1QBP. Moreover, in a clinical cohort of OSCC patients, PA28{gamma} was positively correlated with C1QBP expression and negatively correlated with prognosis. Therefore, C1QBP represents a potential therapeutic target for cancer treatment and prognosis.

cancer biology↗

Acupuncture triggers earlier recovery from ischemic stroke than sham needling in a rat model

Summary paragraphAcupuncture, a traditional Chinese medical treatment that has been practiced for over 2,000 years, is widely used around the world [1]. However, its efficacy and distinction from random stimulation are still being questioned [2, 3]. Over the years, many studies have reported either favorable, neutral or even skeptical outcomes regarding the treatment effect of acupuncture on diverse ailments [4-7]. The major question behind this controversy is whether acupuncture is different from random needle insertion and whether its efficacy can be attributed to the placebo effect [8, 9]. Here, we use micro-positron emission tomography (microPET) imaging in a randomized controlled animal study to show that acupuncture facilitates faster recuperation in comparison to sham acupuncture and blank control. Based on the microPET imaging of subjects undergoing daily acupuncture over two weeks duration, we dynamically monitored the metabolic activity levels in different brain regions and found that both acupoint and non-acupoint stimulation could improve ischemic stroke recovery. This finding is consistent with previous reports that both acupuncture and sham needling show a positive effect in the treatment of diseases [4, 5, 8]. More importantly, we further found that rats receiving acupuncture at Baihui (GV20) and Shuigou (GV26), two commonly used acupoints for stroke rehabilitation based on the concept of the meridian system, showed earlier recovery effects than rats receiving sham needling treatment. This difference mainly appeared in regions involved in motor control and was validated by a balance beam walking test. Our findings, in conjunction with a recent electroacupuncture study that revealed a neuroanatomical pathway to mediate the vagal-adrenal anti-inflammatory axis [10], provide quantitative evidence supporting the specificity of acupoints in acupuncture therapy.

neuroscience↗

Macrophage-derived CCL24 promotes fibrosis and worsens cardiac dysfunction during heart failure

Inflammation is a significant risk factor and contributes to cardiovascular disease by driving both adaptive and maladaptive processes. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. We have previously shown an overall protective function of resident cardiac macrophages after pressure-overloaded injury. However, a subpopulation of resident macrophages also expresses high levels of the profibrotic CC motif chemokine ligand 24 (CCL24), suggesting a dichotomous role in pressure overload-induced cardiac remodeling. Here, we report that following transverse aortic constriction CCL24 knockout (CCL24 KO) mice have improved systolic function, cardiac wall enlargement, as well as increased myocyte surface area and hypertrophy, suggesting that CCL24 disrupts compensatory hypertrophy. TAC-operated CCL24 KO mice also displayed reduced fibrosis and diminished expression of fibrotic genes, implying a pro-fibrotic role for CCL24. Indeed, CCL24 induced the proliferation and activation of primary mouse fibroblasts in a process that required CCR3, the sole G protein-coupled receptor for CCL24. Correspondingly, selective ablation of CCR3 in fibroblasts improved cardiac function and ameliorated fibrosis following pressure overload. Administration of a CCL24 blocking antibody or a CCR3 antagonist both improved cardiac function in pressure-overloaded mice, highlighting the CCL24-CCR3 axis as a potential therapeutic target for heart failure. Finally, CCL24 deficiency improved cardiac function and ameliorated fibrosis during physiological aging. Overall, these results show that macrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, leading to impaired cardiac function in acute and chronic heart failure.

immunology↗

Targeting NOTCH2-JAG1 juxtacrine signaling reverses macrophage-mediated tumor resistance to taxol

Taxanes are widely used in chemotherapy, but primary and acquired resistance limit the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet therapeutic strategies that directly deplete or repolarize macrophages are challenging and with considerable risk of side effects. Here we uncovered that tumor-macrophage interaction can be selectively targeted by inhibiting post-mitotic NOTCH2-JAG1 juxtacrine signaling in the TME, which strongly sensitizes paclitaxel response. Using translatome profiling, we found significant NOTCH2 upregulation during paclitaxel-induced prolonged mitosis. NOTCH2 was subsequently activated in the post-mitotic G1 phase by JAG1 expressed on the neighboring macrophages and tumor cells, which promoted tumor cell survival and upregulated cytokines that recruited JAG1-expressing macrophages, thus generating a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. By targeting this NOTCH2-JAG1 axis using NOTCH2 shRNA or a pan-NOTCH inhibitor, macrophage recruitment and paclitaxel resistance were significantly attenuated in multiple mouse tumor models of ovarian cancer. Clinical samples from paired primary and recurrent ovarian cancer patients also showed significant correlation of higher NOTCH2 expression with worse prognosis. Our results thus point to combining NOTCH2 inhibitor with taxane as an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction in the TME and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.

cancer biology↗

Probing tau citrullination in Alzheimer's disease brains and mouse models of tauopathy

Tauopathies, which include Alzheimers disease (AD) share a common defining factor, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequalae. We uncovered a novel PTM of tau, named citrullination, caused by peptidyl arginine deiminase (PAD) enzymes. PAD induced citrullination irreversibly converts arginine residues to citrulline, producing net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimers disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule binding repeat domain (MBR), and C-terminal domain (C-term) on full length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimers disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher phospho-tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.

neuroscience↗

Activation of two noncanonical R proteins by an insect effector confers plant immunity to aphid infestation

Molecular characterization of resistance genes is crucial for efficiently understanding and fortifying plant immunity against insect herbivores. Here we report that RMES1A and RMES1B proteins confer resistance to the sorghum aphid Melanaphis sorghi when activated by an insect effector MsEF1. Map-based cloning plus genetic analysis of knockout mutants confirm that RMES1A and RMES1B are both required for aphid resistance. Upon aphid attack, RMES1A and RMES1B expression is elevated in the sclerenchyma cells and vascular bundles of leaves; the two proteins interact with MsEF1 in the exocysts, thus upregulating key defense processes such as reactive oxygen species burst. Structural modeling predicts that RMES1A and RMES1B each carry an ATP binding site and two leucine-rich-repeat domains but lack coiled-coil or Toll/Interleukin-1 receptor/resistance domain, thus likely representing a new type of resistance controlling proteins in plants. Our work reveals new genes and mechanisms for further deciphering and improving plant immunity to insect pests.

genetics↗

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

Health is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models. These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension. Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

systems biology↗

A new yeast-based bioreporter for simple, sensitive, and cost-effective detection of dioxin-like compounds

Dioxin-like compounds (DLCs) are environmental xenobiotics that can activate the aryl hydrocarbon receptors (AhR), thereby imposing a significant threat to human health through biomagnifications processes. In this study, a dioxin-activated nano-luminescent Saccharomyces cerevisiae bioreporter, called DnaSc, was developed for simple and rapid detection of DLCs and AhR agonists. The bioreporter used nano-luciferase NLuc as a signal generator to emit bioluminescent signals in response to DLCs without cell lysis. Through optimizing ARNT expression and engineering the aryl hydrocarbon receptor (AhR), the yeast-based bioassay exhibited a detection limit of 10 fM for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within 6 h, making it the most sensitive whole-cell biosensor reported to date. Furthermore, the detection capacity of the DnaSc bioassay for DLCs and AhR agonists was characterized. In summary, the yeast-based bioreporter developed in this study provided a simple, sensitive, and cost-effective method for DLCs detection.

bioengineering↗

Deep generative models generate mRNA sequences with enhanced translation capacity and stability

Despite the tremendous success of messenger RNA (mRNA) COVID-19 vaccines, the extension of this modality to a broader spectrum of diseases necessitates substantial enhancements, particularly in the design of mRNAs with elevated expression levels and extended durability. Here we present GEMORNA, a deep generative model designed to generate novel mRNA coding sequences (CDSs) and untranslated regions (UTRs) with superior translation capacity, comparable to the sophisticated task of language translation and free-form poetry composition with accurate grammar and semantics. Our AI model was trained on an extensive collection of RNA sequences from diverse families, further enhanced with labeled data to refine its performance. Remarkably, we demonstrate that our AI-generated mRNAs exhibited 8.2-fold and 15.9-fold increases in firefly luciferase expression compared to benchmark mRNAs in two different cell types. Additionally, Our AI- designed COVID-19 mRNA vaccine elicited a 4-fold increase in anti-COVID antibody titer in mice relative to BNT162b2. Furthermore, GEMORNAs versatility extends to circular mRNA design, which we facilitated a 27-fold increase in human erythropoietin protein expression in vivo than a systematically optimized benchmark sequence. We also created circular mRNAs with substantial improvements in expression levels, durability and anti-tumor cell cytotoxicity in mRNA-transduced CAR-T cells compared with an experimentally validated benchmark. In summary, GEMORNA generates novel mRNA sequences with significant performance improvements and has the potential to enable a wide range of therapeutic and vaccine applications.

synthetic biology↗

Disruption of sustained attention and orbitofrontal cortex engagement by incoming social media messages vary as a function of problematic social media use

BackgroundSmartphones and social media have become ubiquitous in our lives, and while debates about their negative impact on mental health, addictive potential, and disruptive effects on daily activities have surged, neurobiological evidence remains scarce. Here, we investigated whether the behavioral and neural effects of interference of continuous attention by incoming social media messages on WeChat varies according to its problematic use as assessed via an addiction framework. MethodsN = 60 healthy individuals were stratified based on their level of problematic WeChat usage as measured by the WeChat Addiction Scale (WAS): LOW (15 males and 15 females) and HIGH (15 males and 15 females) addictive tendencies. Participants underwent an AX-Continuous Performance Task (AX-CPT) with WeChat-associated (incoming message) and neutral auditory distractors as well as a no distractor condition. Concurrent functional Near-Infrared Spectroscopy (fNIRS) assessments of the orbitofrontal cortex (OFC) were implemented to determine the underlying neurofunctional mechanisms. ResultsOn the behavioral level the HIGH group demonstrated faster reaction times during the WeChat and no distractor condition compared to the LOW group. Exploratory analyses indicated that the WeChat distraction decreased left lateral OFC activity in the LOW but enhanced activity in this region in the HIGH group. ConclusionAgainst our hypotheses WeChat distraction enhanced behavioral performance specially in individual with a tendency for problematic WeChat use, with the neural data pointing to less suppression of the OFC in individuals with a tendency for problematic usage. Findings underscore the complexity of the potential effects of new technology on daily live and indicate that addiction models might not be simply extendable to problematic social media usage.

neuroscience↗

Occurrence, risk assessment of antibiotics and antimicrobial resistance in Escherichia coli in typical rivers of Sichuan

Worldwide interest has been generated by the presence and distribution of antibiotics and antibiotic resistance genes (ARGs) in rivers. However, there was a dearth of research on the contamination of Sichuan provinces typical rivers with antibiotics. In this study, the residual level of antibiotics in 42 national/provincial sites of 9 rivers was analyzed by UPLC-MS/MS, the ecological risk level was evaluated using risk assessment method, and the drug resistance of E. coli in water was evaluated by Kirby-Bauer method. Redundancy analysis demonstrated how residual antibiotics affect the structure of the microbial community in the Minjiang River basin (RDA). Nine rivers all contained antibiotics. Among them, the MinJiang, TuoJiang, and JiaLingJiang rivers were severely contaminated with antibiotic concentrations ranging from 0.29 to 2233.71 ng/L. The Sichuan Basins antibiotic pollution level was significantly higher when compared to other Sichuan zones, which was consistent with the regions high population density. Additionally, it was discovered that 9.77% of the E. coli isolated from 9 rivers had antibiotic resistance, and more than 5.8% of them had multidrug resistance. Moreover, Norfloxacin, amoxicillin, ampicillin, and tetracycline were the main risk factors for high ecological risk in 26 of the 42 monitoring sites. Additionally, there is a strong correlation between the microbial community change and residual antibiotic. These results offered some reference information regarding the distribution of antibiotics and ARGs in typical rivers in the Chinese province of Sichuan, and this study showed that more attention needs to be paid to antibiotic pollution in Sichuans typical rivers.

microbiology↗

The Hippo/YAP Pathway Mediates the De-differentiation of Corneal Epithelial Cells into Functional Limbal Epithelial Stem Cells In Vivo

Regeneration after tissues injury is often associated with cell fate plasticity, which restores damaged or lost cells. The de-differentiation of corneal epithelial cells (CECs) into functional stem cells after the ablation of innate stem cells, known as limbal epithelial stem cells (LESCs), remains controversial. In this study, we showed the functional maintenance of corneal epithelium after the ablation of innate stem cells, and the regeneration of functional LESCs, which maintained corneal transparency, prevented corneal conjunctivalization and participated in the wound healing. Subsequent intravital lineage tracing revealed that CECs could de-differentiate into active or quiescent LESCs, which functioned as well as their innate counterparts. Furthermore, the de-differentiation of CECs required an intact limbal niche, and the outcome of the competition between conjunctival and corneal epithelium for the limbal niche determined whether the de-differentiation would occur or not. Mechanically, the suppression of YAP signal promoted the de-differentiation of CECs after the ablation of innate stem cells, while the persistent activation of YAP prevented the de-differentiation of CECs after an additional alkali burn to the limbal stroma. These results will pave the way for an alternative approach to treat limbal stem cell deficiency (LSCD) by modulating the de-differentiation of CECs in vivo.

cell biology↗

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples. HIGHLIGHTSO_LIRelapse after remission on TKI can harbor mutations in ABL1, RAS, or neither C_LIO_LIMutations and development-like cell state dictate fitness in residual disease C_LIO_LICo-targeting cell state and ABL1 markedly reduces MRD C_LIO_LIBiophysical measurements provide an integrative, rapid measurement of cell state C_LI

cancer biology↗