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Article ; Online: Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models.

Abboud, Ramzi / Kim, Sena / Staser, Karl / Jayasinghe, Reyka G / Lim, Sora / Amatya, Parmeshwar / Frye, C Corbin / Kopecky, Benjamin / Ritchey, Julie / Gao, Feng / Lavine, Kory / Kreisel, Daniel / DiPersio, John F / Choi, Jaebok

Frontiers in immunology

2023 Volume 14, Page(s) 1264496

Abstract: Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have ... ...

Abstract	Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4
MeSH term(s)	Humans ; Animals ; Mice ; Cyclosporine/therapeutic use ; Graft Rejection/prevention & control ; Heart Transplantation/adverse effects ; Sulfonamides
Chemical Substances	Cyclosporine (83HN0GTJ6D) ; baricitinib (ISP4442I3Y) ; Sulfonamides
Language	English
Publishing date	2023-09-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1264496
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Article ; Online: Cross center single-cell RNA sequencing study of the immune microenvironment in rapid progressing multiple myeloma.

NPJ genomic medicine

2023 Volume 8, Issue 1, Page(s) 3

Abstract: Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by complex interactions with the surrounding bone marrow ( ...

Abstract	Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138
Language	English
Publishing date	2023-01-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2813848-X
ISSN	2056-7944 ; 2056-7944
ISSN (online)	2056-7944
ISSN	2056-7944
DOI	10.1038/s41525-022-00340-x
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Article: LINC00355 regulates p27

Eteleeb, Abdallah M / Thunuguntla, Prasanth K / Gelev, Kyla Z / Tang, Cynthia Y / Rozycki, Emily B / Miller, Alexander / Lei, Jonathan T / Jayasinghe, Reyka G / Dang, Ha X / White, Nicole M / Reis-Filho, Jorge S / Mardis, Elaine R / Ellis, Matthew J / Ding, Li / Silva-Fisher, Jessica M / Maher, Christopher A

NPJ breast cancer

2022 Volume 8, Issue 1, Page(s) 49

Abstract: Late-stage relapse (LSR) in patients with breast cancer (BC) occurs more than five years and up to 10 years after initial treatment and has less than 30% 5-year relative survival rate. Long non-coding RNAs (lncRNAs) play important roles in BC yet have ... ...

Abstract	Late-stage relapse (LSR) in patients with breast cancer (BC) occurs more than five years and up to 10 years after initial treatment and has less than 30% 5-year relative survival rate. Long non-coding RNAs (lncRNAs) play important roles in BC yet have not been studied in LSR BC. Here, we identify 1127 lncRNAs differentially expressed in LSR BC via transcriptome sequencing and analysis of 72 early-stage and 24 LSR BC patient tumors. Decreasing expression of the most up-regulated lncRNA, LINC00355, in BC and MCF7 long-term estrogen deprived cell lines decreases cellular invasion and proliferation. Subsequent mechanistic studies show that LINC00355 binds to MENIN and changes occupancy at the CDKN1B promoter to decrease p27
Language	English
Publishing date	2022-04-13
Publishing country	United States
Document type	Journal Article
ISSN	2374-4677
ISSN	2374-4677
DOI	10.1038/s41523-022-00412-2
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Article ; Online: CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells.

O'Neal, Julie / Ritchey, Julie K / Cooper, Matthew L / Niswonger, Jessica / Sofía González, L / Street, Emily / Rettig, Michael P / Gladney, Susan W / Gehrs, Leah / Abboud, Ramzi / Prior, Julie L / Haas, Gabriel J / Jayasinghe, Reyka G / Ding, Li / Ghobadi, Armin / Vij, Ravi / DiPersio, John F

Leukemia

2022 Volume 36, Issue 6, Page(s) 1625–1634

Abstract: Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a ... ...

Abstract	Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/pathology ; Humans ; Immunotherapy, Adoptive ; Mice ; Multiple Myeloma/pathology ; Receptors, Chimeric Antigen/metabolism ; Signaling Lymphocytic Activation Molecule Family/metabolism ; T-Lymphocytes/metabolism ; Tumor Burden ; Xenograft Model Antitumor Assays
Chemical Substances	Receptors, Chimeric Antigen ; SLAMF7 protein, human ; Signaling Lymphocytic Activation Molecule Family
Language	English
Publishing date	2022-04-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01559-4
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Zs.A 2295: Show issues

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Article ; Online: Evolution and structure of clinically relevant gene fusions in multiple myeloma

Steven M. Foltz / Qingsong Gao / Christopher J. Yoon / Hua Sun / Lijun Yao / Yize Li / Reyka G. Jayasinghe / Song Cao / Justin King / Daniel R. Kohnen / Mark A. Fiala / Li Ding / Ravi Vij

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 12

Abstract: Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance. ...

Abstract	Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.
Keywords	Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution and structure of clinically relevant gene fusions in multiple myeloma

Steven M. Foltz / Qingsong Gao / Christopher J. Yoon / Hua Sun / Lijun Yao / Yize Li / Reyka G. Jayasinghe / Song Cao / Justin King / Daniel R. Kohnen / Mark A. Fiala / Li Ding / Ravi Vij

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 12

Abstract	Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.
Keywords	Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.

Crees, Zachary D / Rettig, Michael P / Jayasinghe, Reyka G / Stockerl-Goldstein, Keith / Larson, Sarah M / Arpad, Illes / Milone, Giulio A / Martino, Massimo / Stiff, Patrick / Sborov, Douglas / Pereira, Denise / Micallef, Ivana / Moreno-Jiménez, Gemma / Mikala, Gabor / Coronel, Maria Liz Paciello / Holtick, Udo / Hiemenz, John / Qazilbash, Muzaffar H / Hardy, Nancy /

Latif, Tahir / García-Cadenas, Irene / Vainstein-Haras, Abi / Sorani, Ella / Gliko-Kabir, Irit / Goldstein, Inbal / Ickowicz, Debby / Shemesh-Darvish, Liron / Kadosh, Shaul / Gao, Feng / Schroeder, Mark A / Vij, Ravi / DiPersio, John F

Nature medicine

2023 Volume 29, Issue 4, Page(s) 869–879

Abstract: Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal ... ...

Abstract	Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34
MeSH term(s)	Adult ; Humans ; Multiple Myeloma/drug therapy ; Transplantation, Autologous ; Prospective Studies ; Heterocyclic Compounds/pharmacology ; Heterocyclic Compounds/therapeutic use ; Hematopoietic Stem Cell Mobilization/methods ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cells/metabolism ; Antigens, CD34/metabolism ; Granulocyte Colony-Stimulating Factor/pharmacology ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Immunologic Factors/therapeutic use
Chemical Substances	Heterocyclic Compounds ; Antigens, CD34 ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; Immunologic Factors
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Clinical Trial, Phase III ; Randomized Controlled Trial ; Multicenter Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02273-z
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

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Article ; Online: Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin.

Liang, Wen-Wei / Lu, Rita Jui-Hsien / Jayasinghe, Reyka G / Foltz, Steven M / Porta-Pardo, Eduard / Geffen, Yifat / Wendl, Michael C / Lazcano, Rossana / Kolodziejczak, Iga / Song, Yizhe / Govindan, Akshay / Demicco, Elizabeth G / Li, Xiang / Li, Yize / Sethuraman, Sunantha / Payne, Samuel H / Fenyö, David / Rodriguez, Henry / Wiznerowicz, Maciej /

Shen, Hui / Mani, D R / Rodland, Karin D / Lazar, Alexander J / Robles, Ana I / Ding, Li

Cancer cell

2023 Volume 41, Issue 9, Page(s) 1567–1585.e7

Abstract: DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of ...

Abstract	DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.
MeSH term(s)	Female ; Humans ; DNA Methylation ; Epigenesis, Genetic ; Multiomics ; Gene Expression Regulation, Neoplastic ; Endometrial Neoplasms/genetics
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2023.07.013
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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Article ; Online: Pollock: fishing for cell states.

Bioinformatics advances

2022 Volume 2, Issue 1, Page(s) vbac028

Abstract: Motivation: The use of single-cell methods is expanding at an ever-increasing rate. While there are established algorithms that address cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a ... ...

Abstract	Motivation: The use of single-cell methods is expanding at an ever-increasing rate. While there are established algorithms that address cell classification, they are limited in terms of cross platform compatibility, reliance on the availability of a reference dataset and classification interpretability. Here, we introduce Pollock, a suite of algorithms for cell type identification that is compatible with popular single-cell methods and analysis platforms, provides a set of pretrained human cancer reference models, and reports interpretability scores that identify the genes that drive cell type classifications. Results: Pollock performs comparably to existing classification methods, while offering easily deployable pretrained classification models across a wide variety of tissue and data types. Additionally, it demonstrates utility in immune pan-cancer analysis. Availability and implementation: Source code and documentation are available at https://github.com/ding-lab/pollock. Pretrained models and datasets are available for download at https://zenodo.org/record/5895221. Supplementary information: Supplementary data are available at
Language	English
Publishing date	2022-05-13
Publishing country	England
Document type	Journal Article
ISSN	2635-0041
ISSN (online)	2635-0041
DOI	10.1093/bioadv/vbac028
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Article ; Online: Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma.

Yao, Lijun / Wang, Julia T / Jayasinghe, Reyka G / O'Neal, Julie / Tsai, Chia-Feng / Rettig, Michael P / Song, Yizhe / Liu, Ruiyang / Zhao, Yanyan / Ibrahim, Omar M / Fiala, Mark A / Fortier, Julie M / Chen, Siqi / Gehrs, Leah / Rodrigues, Fernanda Martins / Wendl, Michael C / Kohnen, Daniel / Shinkle, Andrew / Cao, Song /

Foltz, Steven M / Zhou, Daniel Cui / Storrs, Erik / Wyczalkowski, Matthew A / Mani, Smrithi / Goldsmith, Scott R / Zhu, Ying / Hamilton, Mark / Liu, Tao / Chen, Feng / Vij, Ravi / Ding, Li / DiPersio, John F

Cancer research

2023 Volume 83, Issue 8, Page(s) 1214–1233

Abstract: Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) ... ...

Abstract	Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. Significance: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy.
MeSH term(s)	Humans ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Multiomics ; Proteomics ; Biomarkers, Tumor/genetics ; Gene Expression Profiling/methods
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-1769
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