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Role of Siglec-10/G as a tumor suppressor in B-cells

Award Number: R21AI128598
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2018

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Role of Siglec-10/G as a tumor suppressor in B-cells - PROJECT SUMMARY/ABSTRACT Approximately 80% of B-cell non-Hodgkin's lymphomas are derived from germinal center (GC) B-cells. Somatic hypermutation within GC B-cells is necessary for antibody affinity maturation, but somatic mutations can also drive epigenetic lesions that enhance survival, maintain the hyperproliferative state of GC B-cells, and promote lymphomagenesis. Given the susceptibility of GC B-cells to malignant transformation, it is not surprising that the natural process of selection within the GC is thought to help protect against the selection of malignant clones. Accordingly, a deeper understanding of factors that restrain the GC are needed. Siglec- 10/G (human/mouse ortholog) are members of the Siglec family of inhibitory receptors that recognize sialic acid-containing glycan ligands. Siglec-10/G dampen B-cell activation through the B-cell receptor. In mice, the role of Siglec-G in inhibiting the initial events of B-cell activation have been described, but it is unknown if Siglec-G plays a role at later stages, such as in the GC. Interestingly, an expanded GC compartment is observed in Siglec-G-/- mice, Siglec-G-/- mice develop B-cell lymphomas, and Siglec-10 expression is lost on GC-derived B-cell lymphomas. Taken together, we hypothesize that Siglec-G restrains the GC reaction under healthy conditions and that loss of Sigelc-10/G expression promotes the development of GC-derived B-cell lymphomas due to a poorly controlled GC reaction. Preliminary results support a role for Siglec-G in restraining GC B-cells, as B-cell responses in mixed bone marrow chimeras reveal that Siglec-G-/- GC B-cells gradually outcompete WT GC B-cells. Additional preliminary evidence demonstrates a unique phenotype (increased ICOS expression) in GC T-follicular helper (GC-Tfh) cells within Siglec-G-/- mice, supporting other lines of evidence for a role for Siglec-G in modulating B-T cell interactions. This project aims to investigate a causal relationship between loss of Siglec-G and the development of GC-derived B-cell lymphomas and assess a potential role for Siglec-G in regulating B-T cell interactions. Two independent approaches will be used to test causality between loss of Siglec-G-/-, a dysregulated GC, and the development of GC-derived B- cell lymphomas. In the first approach, Tfh cells will be ablated in Siglec-G-/- mice. In the second approach, Siglec-G expression will be maintained transgenically in an independent mouse model that develops GC- derived B-cell lymphomas and loose Siglec-G expression. To examine a role for Siglec-G as a negative regulator of B-T cell interactions, the ligand specificity of Siglec-G will be dissected in reference to glycans on naïve GC-Tfh CD4+ cells, and glycan ligands on CD4+ T-cells will be manipulated to examine what impact this has on B-T cell interactions. The overall objective of this project is to test the role of Siglec-G as a tumor suppressor in GC B-cells and examine one potential mechanism by which Siglec-G restrains the GC. This knowledge will lead to new insights into the etiology of GC-derived B-cell lymphomas, and potentially offer clues for new treatment strategies, which are especially needed for the incurable FL.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Allergy and Infectious Diseases Research	000	3	3/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $17,370 )
2018	2018	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Allergy and Infectious Diseases Research	002	3	12/19/2017	NON-COMPETING CONTINUATION	$108,000
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	003	1	2/9/2018	NEW	$0
2018	2017	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Allergy and Infectious Diseases Research	001	2	11/28/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$114,480
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	11/28/2017	NEW	-$205,110
														Subtotal = $17,370

Issue Date FY: 2017 ( Subtotal = $336,875 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	12/27/2016	NEW	$336,875
														Subtotal = $336,875

Grand Total All Awards = $354,245

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Role of Siglec-10/G as a tumor suppressor in B-cells

Award Number: R21AI128598

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2018

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