Abstract
The online version of this article contains supplemental material. BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined.We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.
| Original language | English |
|---|---|
| Pages (from-to) | 2522-2531 |
| Number of pages | 10 |
| Journal | Journal of Immunology |
| Volume | 197 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Sep 15 2016 |
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ASJC Scopus subject areas
- Immunology
Cite this
Functional differences between IgM and IgD signaling in chronic lymphocytic leukemia. / Ten Hacken, Elisa; Sivina, Mariela; Kim, Ekaterina; O'Brien, Susan; Wierda, William G.; Ferrajoli, Alessandra; Estrov, Zeev; Keating, Michael J.; Oellerich, Thomas; Scielzo, Cristina; Ghia, Paolo; Caligaris-Cappio, Federico; Burger, Jan A.
In: Journal of Immunology, Vol. 197, No. 6, 15.09.2016, p. 2522-2531.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional differences between IgM and IgD signaling in chronic lymphocytic leukemia
AU - Ten Hacken, Elisa
AU - Sivina, Mariela
AU - Kim, Ekaterina
AU - O'Brien, Susan
AU - Wierda, William G.
AU - Ferrajoli, Alessandra
AU - Estrov, Zeev
AU - Keating, Michael J.
AU - Oellerich, Thomas
AU - Scielzo, Cristina
AU - Ghia, Paolo
AU - Caligaris-Cappio, Federico
AU - Burger, Jan A.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - The online version of this article contains supplemental material. BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined.We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.
AB - The online version of this article contains supplemental material. BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined.We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.
UR - http://www.scopus.com/inward/record.url?scp=84988960544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84988960544&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1600915
DO - 10.4049/jimmunol.1600915
M3 - Article
AN - SCOPUS:84988960544
VL - 197
SP - 2522
EP - 2531
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 6
ER -