B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the US, is an incurable disease of unknown etiology affecting middle-aged and older individuals. Patients with CLL have variable clinical courses: some live for decades without therapy, whereas others succumb in a few years after diagnosis despite treatment. Our data indicate that CLL is a monoclonal disease of autoreactive B cells with receptors for antigen (BCRs) of very restricted structure. BCR structure relates to disease outcome because patients with BCRs without IgVH somatic mutations (U-CLL) have a much more aggressive course than patients with BCRs with somatic mutations (M-CLL). The principles governing the biology of CLL cells are similar to those of systemic autoimmunity. Autoantigens cull susceptible B cells out of the normal repertoire and into the disease process;this autoantigen selection is probably aided by intermittent stimulation by microbes. Autoantigenic drive does not appear to stop at leukemic transformation, and we believe this factor is the most important in determining the fate of CLL cells and also of the patient. For these reasons, defining the specific immunoreactive epitopes of the autoantigens that drive the leukemic process is critical. In our studies we will focus on autoantigens that emerge during cellular apoptosis;these autoantigens can be of native structure or chemically modified during the apoptotic process. The autoantigenic epitopes as well as mimetic epitopes from phage-display libraries will be delineated, key residues involved in epitope-BCR affinity scrutinized, and then altered to obtain variants with greater or lesser binding constants (Aim 1). Because the consequences of autoantigen binding determine leukemic cell fate, it is pivotal to determine these and establish the parameters that decide cell fate. CLL cells will be stimulated with surrogate antigens and native or mimetic epitopes that vary in form (soluble vs. insoluble), valency (monomeric vs. multimeric), and affinity (low, intermediate, and high) for the BCR. Initials studies will focus on the mechanisms whereby low-affinity BCR engagement leads to CLL cell apoptosis (Aim 2). Since in vivo B lymphocytes receive signals from several sources and through multiple pathways, we will look for synergy or antagonism between BCR-mediated signals and those delivered through intracellular Toll- like receptor 9 (Aim 3). The results of these studies will provide a structural and mechanistic understanding of the relevant autoantigens in this disease and how these autoantigens stimulate CLL cells, ultimately impacting on patient survival. They will lay the groundwork for future pre-clinical studies targeting the BCRs and the antigens bound in this incurable disease.

Public Health Relevance

B-cell chronic lymphocytic leukemia is a common, incurable disease, affecting middle-aged and older individuals when they could be enjoying the fruits of their working years. The results of our studies will provide an understanding of how this type of leukemia cell is stimulated to grow. The studies lay the groundwork for future therapies which will target the stimulants or the molecules on the leukemia cells that the stimulants bind.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081554-09
Application #
8269093
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Howcroft, Thomas K
Project Start
2000-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$311,150
Indirect Cost
$123,710
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Hwang, Kwan-Ki; Trama, Ashley M; Kozink, Daniel M et al. (2014) IGHV1-69 B cell chronic lymphocytic leukemia antibodies cross-react with HIV-1 and hepatitis C virus antigens as well as intestinal commensal bacteria. PLoS One 9:e90725
Chen, Shih-Shih; Chiorazzi, Nicholas (2014) Murine genetically engineered and human xenograft models of chronic lymphocytic leukemia. Semin Hematol 51:188-205
Marcatili, Paolo; Ghiotto, Fabio; Tenca, Claudya et al. (2013) Igs expressed by chronic lymphocytic leukemia B cells show limited binding-site structure variability. J Immunol 190:5771-8
Chen, Shih-Shih; Batliwalla, Franak; Holodick, Nichol E et al. (2013) Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling. Proc Natl Acad Sci U S A 110:E1500-7
Cesano, Alessandra; Perbellini, Omar; Evensen, Erik et al. (2013) Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies. Haematologica 98:626-34
Strefford, J C; Sutton, L-A; Baliakas, P et al. (2013) Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 27:2196-9
Liu, Yun; Higgins, Chelsea D; Overstreet, Cathie M et al. (2013) Peptides that bind specifically to an antibody from a chronic lymphocytic leukemia clone expressing unmutated immunoglobulin variable region genes. Mol Med 19:245-52
Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia et al. (2012) Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood 119:4467-75
Hwang, Kwan-Ki; Chen, Xi; Kozink, Daniel M et al. (2012) Enhanced outgrowth of EBV-transformed chronic lymphocytic leukemia B cells mediated by coculture with macrophage feeder cells. Blood 119:e35-44
Chiorazzi, Nicholas; Ferrarini, Manlio (2011) Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 117:1781-91

Showing the most recent 10 out of 39 publications