Biology subjects

Brunner, A. M.

Publications and source records attributed to Brunner, A. M..

4 recordsLinked to original sources

bioRxiv2026

Response to azacitidine and the TIM-3 inhibitor, sabatolimab, in MDS and CMML is associated with distinct immune and antigen-presentation states

Targeting the immune checkpoint TIM-3 is of interest in myeloid neoplasms, yet the hematopoietic and immune changes associated with anti-TIM-3 therapy remain poorly characterized. We used single-cell RNA sequencing to profile bone marrow (BM) and peripheral blood from patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) treated with the hypomethylating agent azacitidine combined with sabatolimab, a monoclonal antibody targeting TIM-3, and integrated Human Cell Atlas reference datasets for comparison. CITE-seq profiling showed that TIM-3 was predominantly expressed on dendritic cells and NK cells, with variable expression across other populations, including CD34 cells and CD8 T cells. At baseline, we identified a population of CD34 myeloid-biased progenitors specific to MDS/CMML samples ("HSPC-like") characterized by inflammatory gene expression programs and features of impaired differentiation. In MDS, elevated baseline HLA class II expression across hematopoietic stem and progenitor cells (HSPCs), HSPC-like cells, and multiple myeloid populations was associated with response. Consistent with this finding, trajectory analysis suggested that nonresponders bypassed HLA class II-high states during myeloid differentiation. In MDS, the presence of distinct CD8 T-cell populations and increased interferon-response programs in CD8 T and NK cells at baseline was also associated with response. In both MDS and CMML, treatment among responders was associated with contraction of BM CD8 and CD4 T-cell populations characterized by type I interferon-responsive and inflammatory programs, including IFIT1, IFIT2, and TNF, along with expansion of a distinct GZMH/IFITM1-expressing cytotoxic CD8 T-cell population. Together, these findings identify baseline antigen-presentation and immune-response programs associated with therapeutic response and reveal coordinated remodeling of myeloid and lymphoid compartments during azacitidine/sabatolimab treatment in MDS and CMML.

cancer biology↗

bioRxiv2025

Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis

Macrophages in the tumor microenvironment exert potent anti-tumorigenic activity through phagocytosis. Yet therapeutics that enhance macrophage phagocytosis have not improved outcomes in clinical trials for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). To systematically identify regulators of phagocytosis, we performed genome-scale CRISPR knockout screens in human leukemia cells co-cultured with human monocyte-derived macrophages. Surprisingly, we found that whereas the classic "dont eat me" signal CD47 inhibited mouse macrophages, it did not inhibit phagocytosis by human macrophages. In contrast, the O-linked glycosylation and sialylation pathways were strong negative regulators of phagocytosis. In AML, the cell surface O-linked glycoprotein CD43 was the major effector of the O-linked glycosylation and sialylation pathways. Genetic deletion or antibody blockade of CD43 enhanced macrophage phagocytosis. This work highlights the importance of using human platforms to identify immune checkpoints, and nominates CD43 as a glyco-immune regulator of human macrophage phagocytosis.

cancer biology↗

bioRxiv2022

CRISPR/Cas9 mutants delineate roles of Populus FT and TFL1/CEN/BFT family members in growth, dormancy release and flowering

Vegetative and reproductive phase change and phenology are economically and ecologically important traits. Trees typically require several years of growth before flowering and once mature, seasonal control of the transition to flowering and flower development is necessary to maintain vegetative meristems and for reproductive success. Members of two related gene subfamilies, FLOWERING LOCUST (FT) and TERMINAL FLOWER1 (TFL1)/CENTRORADIALIS (CEN)/BROTHER OF FT AND TFL1 (BFT), have antagonistic roles in flowering in diverse species and roles in vegetative phenology in trees, but many details of their functions in trees have yet to be resolved. Here, we used CRISPR/Cas9 to generate single and double mutants involving the five Populus FT and TFL1/CEN/BFT genes. ft1 mutants exhibited wild-type-like phenotypes in long days and short days, but after chilling to release dormancy showed delayed bud flush and GA3 could compensate for the ft1 mutation. After rooting and generating some phytomers in tissue culture, both cen1 and cen1ft1 mutants produced terminal as well as axillary flowers, indicating that the cen1 flowering phenotype is independent of FT1. Some axillary meristems initially generated phytomers and in potted plants, the timing of flowering in these shoots correlated with upregulation of FT2 in maturing leaves, suggesting that, in long days, CEN1 antagonizes FT2 promotion of flowering but enables FT2 promotion of shoot growth by maintaining indeterminacy of the shoot apical meristem. CEN1 showed distinct circannual expression patterns in vegetative and reproductive tissues and comparison with the expression patterns of FT1 and FT2 suggest that the relative levels of CEN1 compared to FT1 and FT2 regulate multiple phases of vegetative and reproductive seasonal development.

plant biology↗

bioRxiv2021

HERMES: a molecular formula-oriented method to target the metabolome

Comprehensive metabolome analyses are hampered by low identification rates of metabolites due to suboptimal strategies in MS and MS2 acquisition, and data analysis. Here we present a molecular formula-oriented and peak detection-free method, HERMES, that improves sensitivity and selectivity for metabolite profiling in MS and structural annotation in MS2. An analysis of environmental water, E. coli, and human plasma extracts by HERMES showed increased biological specificity of MS2 scans, leading to improved mass spectral similarity scoring and identification rates when compared to iterative data-dependent acquisition (DDA). HERMES is available as an R package with a user-friendly graphical interface to allow data analysis and interactive tracking of compound annotations.

bioinformatics↗