Sunday, September 7, 2025 9/7/2025

B CELL TRANSFORATION IN FAS AND FASL DEFICIENT MICE

Award Number: R01CA082872
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/02/2001
PERIOD OF PERFORMANCE END DATE: 02/28/2005

Group Awards By:

View Award Description

B CELL TRANSFORATION IN FAS AND FASL DEFICIENT MICE - DESCRIPTION: (Adapted from applicant's abstract) For more than a decade, our laboratory has been investigating the effects on the immune system of inherited mutations in Fas and Fasl that result in inactivation of the Fas apoptosis pathway. These mutations have profound and pleiotropic effects on the immune system in mice and man including the development of systemic autoimmunity and massive lymphoid hyperplasia resulting from the sequestering of anergic T cells, memory phenotype T and B cells and plasma cells. Recently, we observed that mice with Fas (lpr) or Fasl (gld)mutations have an increased risk of developing B cell malignancies. Parallel observations also have been made for ALPS patients with inherited Fas mutations and there is increasing evidence that somatic mutation of Fas is associated with a wide variety of human B lineage tumors. Thus, the Fas pathway appears to have an important anti-oncogenic function in B cells. In BALBgld/gld mice which have mutations in Fasl and a greatly increased risk of plasmacytoid tumors, we observed increased secretion of IL-10 by both activated T cells and the tumors. Abnormal production of IL-10 also has been observed in ALPS patients and is associated with increased disease severity. We hypothesize that germline Fas and Fasl mutations contribute to B cell transformation by creating an environment in which there is chronic B cell activation, increased opportunity for DNA damage, increased survival of mutated B cells and defects in T cell immune surveillance. In this proposal, we will use an in vivo mutagenesis assay employing BALB-gld/gld,lacZ plasmid Tg mice to test the hypothesis that inherent absence of the Fas pathway will result in the spontaneous accumulation of mutated B cells and that the frequency of mutated cells will increase further following chronic oxidative stress. To determine whether autoreactive B cells are selectively targeted for transformation and if antigen selection is occurring in the tumor population, we will examine the tumors for evidence of IgH variable region gene hypermutation and intraclonal variation, restricted use of VH families arid also for antibody specificity. Finally, we will use BALB-gld/gld IL-10 knockout mice to investigate the role of IL- 10 in chronic B cell activation and in the development of systemic autoimmunity and B lymphomas. We anticipate that these studies will provide important new insights into the mechanisms by which germline and somatic Fas mutations contribute to B lymphomagenesis.


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: 2004 ( Subtotal = $233,888 )
2004	2004	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	737 WEST LOMBARD STREET	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Biology Research	000	5	8/31/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$233,888
2004	2004	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Cancer Biology Research	000	4	3/1/2004	NON-COMPETING CONTINUATION	$0
														Subtotal = $233,888

Issue Date FY: 2003 ( Subtotal = $242,865 )
2003	2003	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Cancer Biology Research	000	3		NON-COMPETING CONTINUATION	$242,865
														Subtotal = $242,865

Issue Date FY: 2002 ( Subtotal = $242,865 )
2002	2002	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Cancer Biology Research	000	2	2/28/2002	NON-COMPETING CONTINUATION	$242,865
														Subtotal = $242,865

Issue Date FY: 2001 ( Subtotal = $242,865 )
2001	2001	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Cancer Biology Research	000	1	3/2/2001	NEW	$242,865
														Subtotal = $242,865

Grand Total All Awards = $962,483

Top

All Categories

About

Search

Reports

Data Submission

Award Information

B CELL TRANSFORATION IN FAS AND FASL DEFICIENT MICE

Award Number: R01CA082872

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/02/2001

PERIOD OF PERFORMANCE END DATE: 02/28/2005

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer