title: Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia.
abstract: 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.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Elisa
authors.identifier: 0000-0003-1573-8799
authors.initials: E
authors.lastname: Ten Hacken
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230;
authors.forename: Michael J
authors.identifier: 0000-0002-9121-6450
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, 60590 Frankfurt, Germany; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele and Università Vita-Salute San Raffaele, 20132 Milan, Italy.
authors.forename: Cristina
authors.identifier: 0000-0001-7988-2824
authors.initials: C
authors.lastname: Scielzo
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele and Università Vita-Salute San Raffaele, 20132 Milan, Italy.
authors.forename: Paolo
authors.identifier: 0000-0003-3750-7342
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele and Università Vita-Salute San Raffaele, 20132 Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77230; jaburger@mdanderson.org.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000378:metabolism; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000276:immunology; D054405:Chemokine CCL3 / Q000276:immunology / Q000378:metabolism; D054407:Chemokine CCL4 / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology / Q000378:metabolism*; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000503:physiopathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C084103:BCL6 protein, human; D001798:Blood Proteins; C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C061909:HCLS1 protein, human; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases