Dale Daniel Kim

All Publications

• The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice. The Journal of clinical investigation Tomishima, S. A., Kim, D. D., Porter, N., Guha, I., Dar, A. A., Ortega-Burgos, Y., Roof, J., Fazelinia, H., Spruce, L. A., Thom, C. S., Bowman, R. L., Oliver, P. M. 2025

  Abstract

  The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.

  View details for DOI 10.1172/JCI180913

  View details for PubMedID 40569692

• An Integrated Clinical-Histopathologic Model for Predicting Future Cardiac Allograft Rejection Kim, D. D., Madabhushi, A., Margulies, K., Peyster, E. G. ELSEVIER SCIENCE INC. 2025

  View details for Web of Science ID 001492172200007

• Understanding Reasons for Oral Anticoagulation Nonprescription in Atrial Fibrillation Using Large Language Models. Journal of the American Heart Association Somani, S., Kim, D. D., Perez-Guerrero, E., Ngo, S., Seto, T., Al-Kindi, S., Hernandez-Boussard, T., Rodriguez, F. 2025: e040419

  Abstract

  Rates of oral anticoagulation (OAC) nonprescription in atrial fibrillation approach 50%. Understanding reasons for OAC nonprescription may reduce gaps in guideline-recommended care. We aimed to identify reasons for OAC nonprescription from clinical notes using large language models.We identified all patients and associated clinical notes in our health care system with a clinician-billed visit for atrial fibrillation without another indication for OAC and stratified them on the basis of active OAC prescriptions. Three annotators labeled reasons for OAC nonprescription in clinical notes on 10% of all patients ("annotation set"). We engineered prompts for a generative large language model (Generative Pre-trained Transformer 4) and trained a discriminative large language model (ClinicalBERT) to identify reasons for OAC nonprescription and selected the best-performing model to predict reasons for the remaining 90% of patients ("inference set").A total of 35 737 patients were identified, of which 7712 (21.6%) did not have active OAC prescriptions. A total of 910 notes across 771 patients were annotated. Generative Pre-trained Transformer 4 outperformed ClinicalBERT (macro-F1 score across all reasons of 0.79, compared with 0.69 for ClinicalBERT). Using Generative Pre-trained Transformer 4 on the inference set, 61.1% of notes had documented reasons for OAC nonprescription, most commonly the alternative use of an antiplatelet agent (23.3%), therapeutic inertia (21.0%), and low burden of atrial fibrillation (17.1%).This is the first study using large language models to extract documented reasons for OAC nonprescription from clinical notes in patients with atrial fibrillation and reveals guideline-discordant practices and actionable insights for the development of health system interventions to reduce OAC nonprescription.

  View details for DOI 10.1161/JAHA.124.040419

  View details for PubMedID 40145287

• Predicting right ventricular failure after left ventricular assist device implant: A novel approach. ESC heart failure Livingston, C. E., Kim, D., Serletti, L., Jin, A., Rao, S., Genuardi, M. V., Peyster, E. G. 2025

  Abstract

  Right ventricular (RV) failure (RVF) after left ventricular assist device (LVAD) implant is an important cause of morbidity and mortality. Modern, data-driven approaches for defining and predicting RVF have been under-utilized.Two hundred thirty-two patients were identified with a mean age of 55 years; 40 (17%) were women, 132 were (59%) Caucasian and 74 (32%) were Black. Patients were split between Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Classes 1, 2 and 3 (25%, 38% and 34%, respectively). Within this group, 'provisional RVF' patients were identified, along with 'no RVF' patients. 'No RVF' patients were defined as patients who never demonstrated more than moderate RV dysfunction on a post-LVAD transthoracic echocardiogram (TTE) (ordinal RV function <3), never required an RV assist device (RVAD), were not discharged on sildenafil and were not on a pulmonary vasodilator or inotropic medication at 3 months after LVAD implant. In total, n = 67 patients were defined as 'no RVF'. The remaining patients represented the 'provisional RVF' population (n = 165). Extensive electronic health records queries yielded >1200 data points per patient. Using <1 and >1 month post-LVAD time windows motivated by established, expert-consensus definitions of 'early' and 'late' post-implant RVF, unbiased clustering analysis was performed to identify hidden patient 'phenogroups' within these two established RVF populations. Clusters were compared on post-implant clinical metrics and 1 year outcomes. Lastly, pre-implant metrics were used to generate models for predicting post-implant RVF phenogroup.Within the 'early RVF' time window, distinct 'well' and 'sick' patient phenogroup clusters were identified. These clusters had similar RV function and pulmonary vasodilator usage during the first month after LVAD but differed significantly in heart failure therapy tolerance, renal (P < 0.001) and hepatic (P = 0.013) function, RVAD usage (P = 0.001) and 1 year mortality (P = 0.047). Distinct 'well' and 'sick' phenogroups were also identified in the 'late RVF' time window. These clusters had similar RV function (P = 0.111) and RVAD proportions (P = 0.757) but differed significantly in heart failure medication tolerance, pulmonary vasodilator usage (P = 0.001) and 1 year mortality (P < 0.001). Prediction of phenogroup clusters from the 'early RVF' population achieved an area under the receiver operating characteristic curve (AUROC) of 0.84, with top predictors including renal function, liver function, heart rate and pre-LVAD RV function.Distinct, potentially predictable phenogroups of patients who have significantly different long-term outcomes exist within consensus-defined post-LVAD RVF populations.

  View details for DOI 10.1002/ehf2.15200

  View details for PubMedID 39829406

• Granzyme F: Exhaustion Marker and Modulator of Chimeric Antigen Receptor T Cell-Mediated Cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) Hay, Z. L., Kim, D. D., Cimons, J. M., Knapp, J. R., Kohler, M. E., Quansah, M., Zúñiga, T. M., Camp, F. A., Fujita, M., Wang, X. J., O'Connor, B. P., Slansky, J. E. 2024

  Abstract

  Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models. Granzyme F was one of the most highly upregulated genes in TILs and was exclusively detected in PD1/TIM3 double-positive CD8 TILs. To determine the function of granzyme F and to improve the cytotoxic response to leukemia, we constructed chimeric Ag receptor T cells to overexpress a single granzyme, granzyme F or the better-characterized granzyme A or B. Using these doubly recombinant T cells, we demonstrated that granzyme F expression improved T cell-mediated cytotoxicity against target leukemia cells and induced a form of cell death other than chimeric Ag receptor T cells expressing only endogenous granzymes or exogenous granzyme A or B. However, increasing expression of granzyme F also had a detrimental impact on the viability of the host T cells, decreasing their persistence in circulation in vivo. These results suggest a unique role for granzyme F as a marker of terminally differentiated CD8 T cells with increased cytotoxicity, but also increased self-directed cytotoxicity, suggesting a potential mechanism for the end of the terminal exhaustion pathway.

  View details for DOI 10.4049/jimmunol.2300334

  View details for PubMedID 38416029

• c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+T cell immunity. Nature communications Dar, A. A., Kim, D. D., Gordon, S. M., Klinzing, K., Rosen, S., Guha, I., Porter, N., Ortega, Y., Forsyth, K. S., Roof, J., Fazelinia, H., Spruce, L. A., Eisenlohr, L. C., Behrens, E. M., Oliver, P. M. 2023; 14 (1): 7098

  Abstract

  During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.

  View details for DOI 10.1038/s41467-023-42765-7

  View details for PubMedID 37925424

• PREDICTING TRANSIENT VS SUSTAINED RV FAILURE AFTER LVAD IMPLANTATION: A NOVEL APPROACH Livingston, C. E., Kim, D., Serletti, L., Jin, A., Peyster, E. ELSEVIER SCIENCE INC. 2023: 515

  View details for Web of Science ID 000990866100516

• The ubiquitin ligase Cul5 regulates CD4<SUP>+</SUP> T cell fate choice and allergic inflammation NATURE COMMUNICATIONS Kumar, B., Field, N. S., Kim, D. D., Dar, A. A., Chen, Y., Suresh, A., Pastore, C. F., Hung, L., Porter, N., Sawada, K., Shah, P., Elbulok, O., Moser, E. K., Herbert, D. R., Oliver, P. M. 2022; 13 (1): 2786

  Abstract

  Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.

  View details for DOI 10.1038/s41467-022-30437-x

  View details for Web of Science ID 000798347800015

  View details for PubMedID 35589717

  View details for PubMedCentralID PMC9120070

• The impact of the tumor microenvironment on granzyme production by CD8 T cells Hay, Z., Kim, D., Silva, A., Slansky, J. E. AMER ASSOC IMMUNOLOGISTS. 2020

  View details for Web of Science ID 000589972403128

• <i>IN VIVO</i> MOLECULAR INVESTIGATION OF TAURINE AS A NOVEL THERAPEUTIC APPROACH TO TREATING GLUTATHIONE-DEFICIENT DISEASES IN A MOUSE MODEL OF HOMOCYSTINURIA Kim, D. D., Jiang, H., Maclean, K. BMJ PUBLISHING GROUP. 2019: 232-233

  View details for DOI 10.1136/jim-2018-000939.388

  View details for Web of Science ID 000457712500398