B CLL (B cell chronic lymphocytic leukemia) in humans is a slow accumulative disease of CD5+ B cells that develops in the elderly population, accounting for a third of adult leukemia cases in the United States and Western Europe. Although considered an indolent disease, there is a wide-ranging clinical course. Precise definition of CLL has been difficult due to lack of identification of key cytogenetic abnormalities and uncertainty over its cellular origins and pathogenesis. A long-standing speculation is that antigen-mediated BCR signaling plays a significant role in B CLL development, due to recurrent usage of particular Ig VH family genes. However, such a presumed antigen-driven mechanism could operate at different stages prior to leukemogenesis, during establishment of a B cell pool susceptible to dysregulation, and/or at the point of leukemic initiation/progression. We previously demonstrated that self-antigen mediated BCR signal strength- and quality-dependent CD5 induction occurs in autoreactive B cells using a BCR transgenic (Tg) mouse line. Therefore, CD5+ B CLL may originate from BCR crosslinking-experienced autoreactive B cells. Our autoreactive BCR Tg mouse lines provide a powerful model system to test this possibility. In mice, overexpression of the human TCL1 (T- cell leukemia/lymphoma-1) gene constitutively in B cells as a transgene results in CD5+ B lymphoma/leukemia development in aged mice, with a phenotype resembling human B CLL, at high incidence. By introducing this TCL1Tg into several of our autoreactive BCR mouse models, with or without antigen, we propose to investigate the importance of self-antigen exposure, B cell origin, and the mechanism of progressive B cell leukemogenesis. A focus of this work is to assess the role of the CD5+ autoreactive B cell population, B1, established by self-antigen exposure as an outcome of positive selection, in this CLL model. Although these B cells are normally growth-arrested at the G0/G1 stage, our preliminary data provided evidence for their lymphoma/leukemogenesis potential when TCL1 is overexpressed. This system allows a detailed investigation of lymphoma developmental potential in tissues from early to late stage leukemogenesis, a study not possible in humans.

Public Health Relevance

to Public Health B CLL (B cell chronic lymphocytic leukemia) in humans is a slow accumulative disease of CD5+ B cells that develops in the elderly population, accounting for a third of adult leukemia cases in the United States and Western Europe. A long-standing speculation proposes an autoantigen mediated mechanism for B CLL development. Our autoreactive CD5+ B cell mouse model system allows a detailed investigation of CLL development potential within tissues from early to late stage, and directly tests role of self-antigen, work not possible in humans. Elucidating the mechanism of CLL development in mice will be critically important both for prognosis and for designing rational therapies for dysregulated B cell expansions that can lead to aggressive cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129330-05
Application #
8403711
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Howcroft, Thomas K
Project Start
2009-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$337,720
Indirect Cost
$148,521
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Ichikawa, Daiju; Asano, Masanao; Shinton, Susan A et al. (2015) Natural anti-intestinal goblet cell autoantibody production from marginal zone B cells. J Immunol 194:606-14