Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells
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Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. / Binder, Mascha; Léchenne, Barbara; Ummanni, Ramesh; Scharf, Christan; Balabanov, Stefan; Trusch, Maria; Schlüter, Hartmut; Braren, Ingke; Spillner, Edzard; Trepel, Martin.
In: PLOS ONE, Vol. 5, No. 12, 30.12.2010, p. e15992.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells
AU - Binder, Mascha
AU - Léchenne, Barbara
AU - Ummanni, Ramesh
AU - Scharf, Christan
AU - Balabanov, Stefan
AU - Trusch, Maria
AU - Schlüter, Hartmut
AU - Braren, Ingke
AU - Spillner, Edzard
AU - Trepel, Martin
PY - 2010/12/30
Y1 - 2010/12/30
N2 - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as "subset 1") recognize antigens highly expressed in stromal cells--vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20-45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.
AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as "subset 1") recognize antigens highly expressed in stromal cells--vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20-45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.
KW - Antigens
KW - Calreticulin
KW - Complementarity Determining Regions
KW - Electrophoresis, Gel, Two-Dimensional
KW - HeLa Cells
KW - Humans
KW - Immunoglobulin G
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Leukocytes, Mononuclear
KW - Microscopy, Fluorescence
KW - Receptors, Antigen, B-Cell
KW - Recombinant Proteins
KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
KW - Stromal Cells
KW - Vimentin
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0015992
DO - 10.1371/journal.pone.0015992
M3 - SCORING: Journal article
C2 - 21209908
VL - 5
SP - e15992
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 12
ER -