title: Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling.
abstract: (Auto)antigen engagement by the B-cell receptor (BCR) and possibly the sites where this occurs influence the outcome of chronic lymphocytic leukemia (CLL). To test if selection for autoreactivity leads to increased aggressiveness and if this selection plays out equally in primary and secondary tissues, we used T-cell leukemia (TCL)1 cells reactive with the autoantigen phosphatidylcholine (PtC). After repeated transfers of splenic lymphocytes from a single mouse with oligoclonal PtC-reactive cells, outgrowth of cells expressing a single IGHV-D-J rearrangement and superior PtC-binding and disease virulence occurred. In secondary tissues, increased PtC-binding correlated with enhanced BCR signaling and cell proliferation, whereas reduced signaling and division of cells from the same clone was documented in cells residing in the bone marrow, blood, and peritoneum, even though cells from the last site had highest surface membrane IgM density. Gene-expression analyses revealed reciprocal changes of genes involved in BCR-, CD40-, and PI3K-signaling between splenic and peritoneal cells. Our results suggest autoantigen-stimulated BCR signaling in secondary tissues promotes selection, expansion, and disease progression by activating pro-oncogenic signaling pathways, and that--outside secondary lymphoid tissues--clonal evolution is retarded by diminished BCR-signaling. This transferrable, antigenic-specific murine B-cell clone (TCL1-192) provides a platform to study the types and sites of antigen-BCR interactions and genetic alterations that result and may have relevance to patients.
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.forename: Franak
authors.initials: F
authors.lastname: Batliwalla
authors.forename: Nichol E
authors.initials: NE
authors.lastname: Holodick
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Sophia
authors.initials: S
authors.lastname: Yancopoulos
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000503:physiopathology*; D017710:Lymphocyte Transfusion; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010713:Phosphatidylcholines / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D012641:Selection, Genetic; D015398:Signal Transduction / Q000502:physiology*; D060152:V(D)J Recombination
chemical_list: D001324:Autoantigens; D010713:Phosphatidylcholines; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell; C490393:Tcl1 protein, mouse
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