Biology subjects

Kong, G. L.

Publications and source records attributed to Kong, G. L..

3 recordsLinked to original sources

bioRxiv2022

CITE-Viz: Replicating the Interactive Flow Cytometry Workflow in CITE-Seq

SummaryThe rapid advancement of new genomic sequencing technology has enabled the development of multi-omic single-cell sequencing assays. These assays profile multiple modalities in the same cell and can often yield new insights not revealed with a single modality. For example, CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) simultaneously profiles the single-cell RNA transcriptome and the surface protein expression. The extra dimension of surface protein markers can be used to further identify cell clusters - an essential step for downstream analyses and interpretation. Additionally, multi-dimensional datasets like CITE-Seq require nuanced visualization methods to accurately assess the data. To facilitate cell cluster classification and visualization in CITE-Seq, we developed CITE-Viz. CITE-Viz is a single-cell visualization platform with a custom module that replicates the interactive flow-cytometry gating workflow. With CITE-Viz, users can investigate CITE-Seq specific quality control (QC) metrics, view multi-omic co-expression feature plots, and classify cell clusters by iteratively gating on the abundance of cell surface markers. CITE-Viz was developed to make multi-modal single-cell analysis accessible to a wide variety of biologists, with the aim to discover new insights into their data and to facilitate novel hypothesis generation. Availability and ImplementationCITE-Viz installation and usage instructions can be found in the GitHub repository https://github.com/maxsonBraunLab/CITE-Viz Contactmaxsonj@ohsu.edu Supplementary InformationDown-sampled peripheral blood mononuclear dataset (Hao et al. 2021): https://bit.ly/3vxbhfW

bioinformatics↗

bioRxiv2021

Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs--most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by epigenetic modulatory drugs. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs. Statement of SignificanceSETBP1 is frequently mutated in chronic neutrophilic leukemia, but its role in the biology of this disease is unclear. We find that mutant SETBP1 enhances transcription of Myc and Myc target genes to promote aggressive disease biology, and that these oncogenic transcriptional programs can be reversed by epigenetic modulatory drugs.

cancer biology↗

bioRxiv2021

PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia

Activating mutations in the KIT tyrosine receptor kinase confer an adverse prognosis for patients with acute myeloid leukemia (AML). Outside of bone marrow transplantation, treatment options are limited. Here we demonstrate combined KIT and LSD1 inhibition produces synergistic cell death against KIT mutant AML cells. This combination suppresses MYC expression to drive cell cycle exit and apoptosis. This decreased MYC expression results from a loss of PU.1 binding at downstream MYC enhancers. The drug combination also inactivates PI3K/AKT/GSK3a/b signaling to decrease MYC protein abundance. KIT-mutant AML cells rapidly adapt to KIT inhibitor monotherapy by restoring PI3K/AKT activity, but cannot when treated with combined KIT and LSD1 inhibitor. In addition, we validate MYC suppression as a mechanism of synergy in KIT-mutant AML patient samples. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML. Statement of significanceEffective treatment options for AML are limited. We describe the synergistic response to combined KIT and LSD1 inhibition in KIT-mutant AML and identify key biomarkers of drug response. The specificity and efficacy of this combination in cell lines and patient samples provides rationale for investigation in early phase clinical trials.

cancer biology↗