Associations of quantitative contrast sensitivity with vascular metrics on widefield swept-source OCT angiography across stages of diabetic retinopathy.

PURPOSE: To investigate structure-function associations between contrast sensitivity (CS) and widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vascular metrics across stages of non-proliferative (NPDR) and proliferative diabetic retinopathy (PDR), without diabetic macular oedema. METHODS: Prospective cross-sectional study in 140 eyes of 99 patients: 33 mild NPDR, 24 moderate/severe NPDR, 15 PDR, 33 diabetic without DR (DMnoDR) and 46 control eyes. Mixed-effects multivariable regression models to evaluate associations between quantitative contrast sensitivity function (Adaptive Sensory Technology) and vessel density (VD) and vessel skeletonised density (VSD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) on same-day imaging with WF SS-OCTA (Plex Elite 9000, Carl Zeiss Meditec). RESULTS: Standardised ß coefficients for area under the logarithm of contrast sensitivity function curve (AULCSF) versus visual acuity (VA) at 3×3 mm scans: SCP VSD (ß=0.32, p<0.001 vs -0.18, p=0.044), DCP VSD (ß=0.30, p<0.001 vs -0.21, p=0.02), SCP VD (ß=0.25, p=0.004 vs -0.13, p=0.129), DCP VD (ß=0.26, p=0.003 vs -0.19, p=0.034). AULCSF was significantly reduced in mild NPDR (ß=-0.28, p<0.001) and DMnoDR (ß=-0.19, p=0.005) versus controls, while VA was not significantly different. AULCSF performed better than VA in differentiating between controls and DMnoDR (0.69 vs 0.50), controls and mild NPDR (0.76 vs 0.61) and controls and moderate/severe NPDR (0.89 vs 0.73). CONCLUSIONS: DR-induced microvascular changes on OCTA are associated with larger changes on CS than in VA. CS is affected earlier than VA in the course of DR and performed better in discriminating between controls, DMnoDR and across DR stages.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.

Examining factors related to low performance of predicting remission in participants with major depressive disorder using neuroimaging data and other clinical features.

Major depressive disorder (MDD), a prevalent mental health issue, affects more than 8% of the US population, and almost 17% in the young group of 18-25 years old. Since Covid-19, its prevalence has become even more significant. However, the remission (being free of depression) rates of first-line antidepressant treatments on MDD are only about 30%. To improve treatment outcomes, researchers have built various predictive models for treatment responses and yet none of them have been adopted in clinical use. One reason is that most predictive models are based on data from subjective questionnaires, which are less reliable. Neuroimaging data are promising objective prognostic factors, but they are expensive to obtain and hence predictive models using neuroimaging data are limited and such studies were usually in small scale (N<100). In this paper, we proposed an advanced machine learning (ML) pipeline for small training dataset with large number of features. We implemented multiple imputation for missing data and repeated K-fold cross validation (CV) to robustly estimate predictive performances. Different feature selection methods and stacking methods using 6 general ML models including random forest, gradient boosting decision tree, XGBoost, penalized logistic regression, support vector machine (SVM), and neural network were examined to evaluate the model performances. All predictive models were compared using model performance metrics such as accuracy, balanced accuracy, area under ROC curve (AUC), sensitivity and specificity. Our proposed ML pipeline was applied to a training dataset and obtained an accuracy and AUC above 0.80. But such high performance failed while applying our ML pipeline using an external validation dataset from the EMBARC study which is a multi-center study. We further examined the possible reasons especially the site heterogeneity issue.

Comparative adherence of macitentan versus ambrisentan and bosentan in Australian patients with pulmonary arterial hypertension: a retrospective real-world database study.

AIM: Bosentan, ambrisentan, and macitentan are endothelin receptor antagonists (ERAs), currently available in Australia for treatment of pulmonary arterial hypertension (PAH). This study assessed the comparative adherence of these ERAs for PAH in Australian patients. METHODS: This retrospective, observational study used data for adults with PAH from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset (01/2006-10/2020). The primary outcome was treatment adherence (i.e. receiving ≥80% of ERA doses over 12 months). Secondary outcomes were time to treatment change (add-on or switch) and overall survival. RESULTS: The study included 436 patients who took bosentan (n = 200), ambrisentan (n = 69), or macitentan (n = 167). Treatment adherence was significantly greater in patients who received macitentan (65.3%) versus ambrisentan (56.5%) and bosentan (58.0%), with odds ratios (ORs; 95% CI) of 0.51 (0.30-0.88; p = 0.016) for bosentan versus macitentan and 0.48 (0.24-0.96; p = 0.037) for ambrisentan versus macitentan. The median time to treatment change was 47.2 and 43.4 months for bosentan and ambrisentan, respectively (not calculated for macitentan because of insufficient duration of data). LIMITATIONS AND CONCLUSIONS: Real-world data for Australian patients with PAH showed that treatment adherence for ERAs was suboptimal. Adherence was higher for macitentan compared with ambrisentan and bosentan.

Widefield, Swept-Source Optical Coherence Tomography Angiography Metrics as Predictors of Anti-VEGF Treatment in Retinal Vein Occlusions.

BACKGROUND AND OBJECTIVE: Our objective was to assess baseline widefield swept-source optical coherence tomography angiography (WF SSOCTA) microvascular metrics as predictors for the number of anti-vascular endothelial growth factor (VEGF) injections and visual acuity (VA) at 12-months follow-up in patients with retinal vein occlusion (RVO). PATIENTS AND METHODS: This was a prospective study including 49 RVO eyes from 49 patients who had not received an anti-VEGF injection for at least 3 months prior to imaging. Microvascular metrics from 6×6-mm and 12×12-mm angiograms were assessed using linear regression models, adjusting for age. RESULTS: Reductions in the vessel density (VD) and vessel skeletonized density (VSD) vascular metrics were associated both with a higher number of anti-VEGF injections at all follow-up time points and reduced VA 12 months after imaging in all RVO eyes. CONCLUSIONS: WF SS-OCTA VD and VSD micro-vascular metrics at baseline can prognosticate VA and number of anti-VEGF injections required at 3, 6, and 12 months in RVO eyes. [Ophthalmic Surg Lasers Imaging Retina 2024;55:xx-xx.].

Generation of induced pluripotent stem cell line from a patient suffering from arterial calcification due to deficiency of CD73 (ACDC).

Arterial calcification due to deficiency of CD73 (ACDC) is an adult onset, rare genetic vascular disorder signified by calcium deposition in lower extremity arteries and joints of hands and feet. Mutations in NT5E gene has been shown to be responsible for the inactivation of enzyme CD73 causing calcium buildup. Here, we report a iPSC line generated from a patient showing signs of ACDC and carrying a missense mutation in NT5E (c.1126A→G,p.T376A) gene. This iPSC line shows normal morphology, pluripotency, karyotype, and capability to differentiate into three germ layers, making it useful for disease modeling and investigating pathological mechanisms of ACDC.

Impact of Invasive Escherichia Coli Disease on Clinical Outcomes and Medical Resource Utilization Among Asian Patients in the United States.

INTRODUCTION: Invasive Escherichia coli disease (IED) can lead to sepsis and death and is associated with a substantial burden. Yet, there is scarce information on the burden of IED in Asian patients. METHODS: This retrospective study used US hospital data from the PINC AI™ Healthcare database (October 2015-March 2020) to identify IED cases among patients aged ≥ 60 years. IED was defined as a positive E. coli culture in blood or other normally sterile body site (group 1 IED) or positive culture of E. coli in urine with signs of sepsis (group 2 IED). Eligible patients with IED were classified into Asian and non-Asian cohorts based on their reported race. Entropy balancing was used to create cohorts with similar characteristics. Outcomes following IED were descriptively reported in the balanced cohorts. RESULTS: A total of 646 Asian and 19,127 non-Asian patients with IED were included (median age 79 years; 68% female after balancing). For both cohorts, most IED encounters had community-onset (> 95%) and required hospitalization (Asian 96%, mean duration 6.9 days; non-Asian 95%, mean duration 6.8 days), with frequent admission to intensive care (Asian 35%, mean duration 3.3 days; non-Asian 34%, mean duration 3.5 days), all standardized differences [SD] < 0.20. Compared to non-Asian patients, Asian patients were more likely to be discharged home (54% vs. 43%; SD = 0.22), and less likely to be discharged to a skilled nursing facility (24% vs. 31%; SD = 0.16). In-hospital fatality rates during the IED encounter were similar across cohorts (Asian 9%, non-Asian 10%; SD = 0.01). Most E. coli isolates showed resistance to ≥ 1 antibiotic (Asian 61%; non-Asian 64%) and 36% to ≥ 3 antibiotic classes (all SD < 0.20). CONCLUSION: IED is associated with a substantial burden, including need for intensive care and considerable mortality, in Asian patients in the USA that is consistent with that observed for non-Asian patients.

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Window Treatment-Bringing Art and Joy to Hospital Rooms.

This Arts and Medicine feature coauthored by a patient and her hospital clinicians describes the use of hand-drawn window art in hospital rooms as a way to bring color and creativity into inpatient settings and build community among hospital staff and patients.

Epigenetic reprogramming shapes the cellular landscape of schwannoma.

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.

Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.

Vascular homeostasis and pathophysiology are tightly regulated by mechanical forces generated by hemodynamics. Vascular disorders such as atherosclerotic diseases largely occur at curvatures and bifurcations where disturbed blood flow activates endothelial cells while unidirectional flow at the straight part of vessels promotes endothelial health. Integrated analysis of the endothelial transcriptome, the 3D epigenome, and human genetics systematically identified the SNP-enriched cistrome in vascular endothelium subjected to well-defined atherosclerosis-prone disturbed flow or atherosclerosis-protective unidirectional flow. Our results characterized the endothelial typical- and super-enhancers and underscored the critical regulatory role of flow-sensitive endothelial super-enhancers. CRISPR interference and activation validated the function of a previously unrecognized unidirectional flow-induced super-enhancer that upregulates antioxidant genes NQO1, CYB5B, and WWP2, and a disturbed flow-induced super-enhancer in endothelium which drives prothrombotic genes EDN1 and HIVEP in vascular endothelium. Our results employing multiomics identify the cis-regulatory architecture of the flow-sensitive endothelial epigenome related to atherosclerosis and highlight the regulatory role of super-enhancers in mechanotransduction mechanisms.

Widefield swept-source optical coherence tomography angiography metrics associated with neovascular glaucoma in patients with proliferative diabetic retinopathy.

PURPOSE: To explore the association between widefield swept-source optical coherence tomography angiography (WF SS-OCTA) metrics, including nonperfusion area (NPA) and neovascularization (NV), and presence of neovascular glaucoma (NVG) in patients with proliferative diabetic retinopathy (PDR). METHODS: A prospective, cross-sectional study was conducted from November 2018 to February 2020. A total of 85 eyes of 60 PDR patients without NVG and 9 eyes of 8 PDR patients with NVG were included. Retinal ischemic parameters (NPA; ischemia index [NPA/total retinal area]) and NV features (NV number; NV area; NV vessel density) were evaluated. Foveal avascular zone (FAZ), macular thickness/volume, and choroidal thickness/volume were obtained using the Zeiss ARI Network. WF SS-OCTA retinal and choroidal metrics, systemic, and ocular parameters were screened using Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression for variable selection. Firth's bias-reduced logistic regression (outcome: presence of NVG) was subsequently used to identify parameters associated with NVG. RESULTS: After LASSO variable selection, 8 variables were significantly associated with the presence of NVG: DM duration (years), insulin (yes/no), best-corrected visual acuity (BCVA) (logMAR), IOP, ischemia index, skeletonized vessel density, macular thickness (inner inferior, outer temporal regions). Firth's bias-reduced logistic regression showed ischemia index (odds ratio [OR]=13.2, 95% confidence interval [CI]:5.3-30.7, P<0.001) and BCVA (OR=5.8, 95%CI:1.2-28.8, P<0.05) were associated with the presence of NVG. NV metrics, FAZ, and choroidal parameters were not related to NVG. CONCLUSIONS: Retinal ischemia but not NV was associated with the presence of NVG in patients with PDR using WF SS-OCTA. Larger, longitudinal studies are needed to validate imaging biomarkers associated with diabetic NVG.

Pilot applications of GPT-4 in radiation oncology: Summarizing patient symptom intake and targeted chatbot applications.

This study explores using GPT-4 for radiation toxicity monitoring in prostate cancer treatments. Two methods were tested: a summarization method and a chatbot interface. Surveyed radiation oncologists preferred the summarization method for its accuracy and potential for adoption (median rating 8 vs 4, p =.002). Both methods saved time.

Test-retest repeatability and agreement of the quantitative contrast sensitivity function test: towards the validation of a new clinical endpoint.

PURPOSE: The purpose of this study is to investigate test-retest reliability and agreement of the quantitative contrast sensitivity function test (qCSF) in the retina clinic. METHODS: A total of 121 right eyes of 121 patients were tested and consecutively re-tested with qCSF in the retina clinic. Outcomes included area under the logarithm of contrast sensitivity function curve (AULCSF), contrast acuity, and contrast sensitivity thresholds at 1-18 cycles per degree (cpd). Test-retest means were compared with paired t-test, variability was compared with the Brown-Forsythe test, and intraclass correlation coefficient (ICC) and Bland Altman plots evaluated reliability and agreement. RESULTS: Mean test-retest differences for all qCSF metrics ranged from 0.02 to 0.05 log units without statistically significant differences in variability. Standard deviations ranged from 0.08 to 0.14. Coefficients of repeatability ranged from 0.16 to 0.27 log units. ICC > 0.9 for all metrics except 1cpd (ICC = 0.84, all p < 0.001); AULCSF ICC = 0.971. CONCLUSION: qCSF-measured contrast sensitivity shows great test-retest repeatability and agreement in the retina clinic.

Validating the Prognostic Utility of the ABCD-GENE Score in Asian Patients with Acute Coronary Syndrome Patients on Clopidogrel.

Background: The ABCD-GENE score, which links cytochrome P450 2C19 (CYP2C19) phenotype and high platelet reactivity (HPR) to the risk of major adverse cardiovascular events (MACE) in clopidogrel users, has been validated in white and Japanese populations. The prognostic implications of the score in other Asian cohorts, however, have been largely unchartered. The aim of this study was to validate the prognostic utility of the ABCD-GENE score in a heterogeneous Asian acute coronary syndrome (ACS) cohort. Methods and Results: In this single-centre, retrospective cohort evaluation of 423 ACS patients, the objectives were to characterise the best cut-off score for MACE prognostication by comparing the adjusted 1-year risk of MACE between groups above and below the candidate cut-off scores using Cox regression; and for on-clopidogrel HPR prediction using receiver operating characteristic (ROC) analysis and Youden's index. In the adjusted Cox model, an ABCD-GENE score cut-off at 10 points significantly predicts the 1-year risk of MACE (adjusted HR 3.771; 95% CI [1.041-13.661]). Female sex, baseline LDL, history of ACS and angiotensin receptor blocker use were additional independent predictors of MACE. On ROC analysis the ideal cut-off for HPR prediction was 7 points. However, that did not independently predict the 1-year risk of MACE (adjusted HR 1.595; 95% CI [0.425-5.989]). Conclusion: The original ABCD-GENE score 10-point cut-off moderately predicts MACE in a heterogeneous, Asian ACS population at 1 year. Additional predictors of MACE were also identified in the present cohort, and these findings should be prospectively validated in larger ACS cohorts.

Risk Factors Associated with Cystoid Macular Edema among Patients Undergoing Primary Repair of Rhegmatogenous Retinal Detachment.

PURPOSE: To investigate predictors of the development and resolution of cystoid macular edema (CME) after rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective cross sectional study. SUBJECTS: Patients who underwent primary repair of uncomplicated RRD. METHODS: Demographics, ophthalmic history, visual acuity, RRD features, time to development/resolution of CME, OCT characteristics of CME/epiretinal membrane (ERM), type of surgery, and treatments were collected. Logistic regressions were used to identify predictors of CME development and resolution. MAIN OUTCOME MEASURES: Predictors of CME development and resolution. RESULTS: A total of 708 eyes were included, of which 55 (7.8%) developed CME. Factors associated with an increased risk of CME development included total number of retinal detachment surgeries (odds ratio [OR] 1.66 [1.24-2.23], P < 0.001), prior intraocular surgery (OR 4.43 [1.19-16.51], P = 0.03), and presence of ERM after surgery (OR 4.49 [2.30-8.74], P < 0.001). Patients undergoing pars plana vitrectomy (PPV) were more likely to develop CME compared with patients undergoing scleral buckling (SB; OR 3.09 [1.18-8.10], P = 0.02). A longer average time to CME detection was associated with lower CME resolution (OR 0.94 [0.89-0.998], P = 0.04). In patients who developed an ERM postsurgically, those who developed CME after ERM had a lower rate of resolution compared with those who developed CME before ERM (P = 0.03). CONCLUSIONS: Cystoid macular edema may be more likely to develop in patients undergoing PPV than SB, those who underwent more surgeries for RRD repair, those who had prior intraocular surgery, or those who developed an ERM after RRD repair. Resolution of CME may be affected by the time to detection of CME and ERM development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.