Biology subjects

Griffin, G. K.

Publications and source records attributed to Griffin, G. K..

6 recordsLinked to original sources

bioRxiv2025

Early persistence of recipient stem-cells and T-cell dysregulation are associated with relapse after transplant in AML/MDS

Hematopoietic stem cell transplantation (HSCT) offers the best curative option for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), yet relapse remains common. Current relapse detection methods are often too late for effective intervention. To identify earlier predictors and therapeutic targets, we performed longitudinal single-cell RNA and T cell receptor (TCR) sequencing of bone marrow from 33 AML/MDS patients during post-transplant immune reconstitution, comparing those who relapsed to those who remained in remission. Persistence of recipient hematopoietic stem and progenitor cells (HSPCs) in the marrow was associated with relapse months later. These residual recipient HSPCs harbored copy number variations (CNVs), supporting their leukemic origin, and overexpressed PRAME and CALCRL compared to coexisting donor HSPCs. Further, in a subset of TP53-mutant disease, low TCR diversity with skewing toward dominant clonotypes foreshadowed relapse. These findings lay the groundwork for improved relapse prediction and nominate therapeutic targets for early post-transplant intervention.

cancer biology↗

bioRxiv2024

Tissue and cellular spatiotemporal dynamics in colon aging

Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects, but many of the underlying molecular cues remain unclear. Here, we built a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing [~]1,500 mouse gut tissues profiled by spatial transcriptomics and [~]400,000 single nucleus RNA-seq profiles. We developed a new computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region, and sex, by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identified cellular and molecular gradients along the adult colonic tract and across the main crypt axis, and multicellular programs associated with aging in the large intestine. Our multi-modal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.

systems biology↗

bioRxiv2021

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasms (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.

immunology↗

bioRxiv2021

Mitochondrial variant enrichment from high-throughput single-cell RNA-seq resolves clonal populations

Reconstructing lineage relationships in complex tissues can reveal mechanisms underlying development and disease. Recent methods combine single-cell transcriptomics with mitochondrial DNA variant detection to establish lineage relationships in primary human cells, but are not scalable to interrogate complex tissues. To overcome this limitation, here we develop a technology for high-confidence detection of mitochondrial mutations from high-throughput single-cell RNA-sequencing. We use the new method to identify skewed immune cell expansions in primary human clonal hematopoiesis.

genomics↗

bioRxiv2020

Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. STATEMENT OF SIGNIFICANCESex bias in cancer is well recognized but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.

cancer biology↗

bioRxiv2019

The enteric nervous system of the human and mouse colon at a single-cell resolution

As the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.

genomics↗