title: Induction of malignant plasma cell proliferation by eosinophils.
abstract: The biology of the malignant plasma cells (PCs) in multiple myeloma (MM) is highly influenced by the bone marrow (BM) microenvironment in which they reside. More specifically, BM stromal cells (SCs) are known to interact with MM cells to promote MM cell survival and proliferation. By contrast, it is unclear if innate immune cells within this same space also actively participate in the pathology of MM. Our study shows for the first time that eosinophils (Eos) can contribute to the biology of MM by enhancing the proliferation of some malignant PCs. We first demonstrate that PCs and Eos can be found in close proximity in the BM. In culture, Eos were found to augment MM cell proliferation that is predominantly mediated through a soluble factor(s). Fractionation of cell-free supernatants and neutralization studies demonstrated that this activity is independent of Eos-derived microparticles and a proliferation-inducing ligand (APRIL), respectively. Using a multicellular in vitro system designed to resemble the native MM niche, SCs and Eos were shown to have non-redundant roles in their support of MM cell growth. Whereas SCs induce MM cell proliferation predominantly through the secretion of IL-6, Eos stimulate growth of these malignant cells via an IL-6-independent mechanism. Taken together, our study demonstrates for the first time a role for Eos in the pathology of MM and suggests that therapeutic strategies targeting these cells may be beneficial.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minneapolis, USA.
authors.forename: Tina W
authors.initials: TW
authors.lastname: Wong
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Hanson
authors.forename: Denise K
authors.initials: DK
authors.lastname: Walters
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Arendt
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology*; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology*; D012995:Solubility; D017154:Stromal Cells / Q000473:pathology; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D053668:Syndecan-1
references.citation: Blood. 1989 May 15;73(7):1915-24
references.pmid: 2713508
references.citation: Blood. 2005 Aug 15;106(4):1407-14
references.pmid: 15878977
references.citation: Trends Immunol. 2011 Dec;32(12):595-602
references.pmid: 22001488
references.citation: J Biomed Biotechnol. 2012;2012:157496
references.pmid: 23093834
references.citation: Leuk Lymphoma. 2007 Dec;48(12):2323-9
references.pmid: 18067006
references.citation: Eur J Immunol. 2012 Jan;42(1):130-7
references.pmid: 22057654
references.citation: Eur J Haematol. 1992 Oct;49(4):192-8
references.pmid: 1464362
references.citation: Blood. 1993 Jun 15;81(12):3382-7
references.pmid: 8507875
references.citation: Am J Clin Pathol. 1995 May;103(5):583-7
references.pmid: 7741103
references.citation: Immunol Lett. 2011 Dec 30;141(1):145-6
references.pmid: 21864577
references.citation: Nat Immunol. 2008 Jul;9(7):733-42
references.pmid: 18516038
references.citation: J Immunol. 2010 Dec 15;185(12):7180-5
references.pmid: 21068399
references.citation: N Engl J Med. 2011 Mar 17;364(11):1046-60
references.pmid: 21410373
references.citation: Blood. 2008 Sep 1;112(5):1931-41
references.pmid: 18567838
references.citation: Blood. 2008 Mar 1;111(5):2516-20
references.pmid: 17975015
references.citation: Cancer Res. 1993 Nov 1;53(21):5320-7
references.pmid: 8221668
references.citation: Blood. 2008 Mar 1;111(5):2755-64
references.pmid: 18180376
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: J Immunol Methods. 2013 Jan 31;387(1-2):130-9
references.pmid: 23085531
references.citation: Leukemia. 1996 May;10(5):866-76
references.pmid: 8656685
references.citation: Br J Haematol. 2005 Apr;129(2):248-56
references.pmid: 15813853
references.citation: Annu Rev Immunol. 2006;24:147-74
references.pmid: 16551246
references.citation: Blood. 2001 Apr 15;97(8):2522-3
references.pmid: 11290618
references.citation: Blood Cancer J. 2012 Sep 14;2:e91
references.pmid: 22983434
references.citation: Semin Hematol. 2012 Apr;49(2):138-48
references.pmid: 22449624
references.citation: Blood. 2010 Sep 16;116(11):1867-75
references.pmid: 20538807
references.citation: J Immunol. 2002 Oct 15;169(8):4213-21
references.pmid: 12370351
references.citation: J Immunol. 2008 Mar 15;180(6):3655-9
references.pmid: 18322170
references.citation: J Immunother. 2007 Jan;30(1):16-28
references.pmid: 17198080
references.citation: Nat Immunol. 2011 Feb;12(2):151-9
references.pmid: 21217761
references.citation: Mayo Clin Proc. 1987 Nov;62(11):969-77
references.pmid: 3118117
references.citation: Oncoimmunology. 2012 May 1;1(3):388-389
references.pmid: 22737625
references.citation: Blood. 2004 Mar 15;103(6):2308-15
references.pmid: 14615378
references.citation: Br J Haematol. 2012 Aug;158(3):336-46
references.pmid: 22583117
references.citation: J Exp Med. 2006 Aug 7;203(8):1859-65
references.pmid: 16880256
references.citation: Br J Haematol. 1986 Oct;64(2):271-5
references.pmid: 3535868
references.citation: Cancer Res. 2012 Dec 15;72(24):6393-402
references.pmid: 23066034
references.citation: Curr Opin Support Palliat Care. 2012 Sep;6(3):330-6
references.pmid: 22871979
references.citation: Scand J Immunol. 2011 Jun;73(6):508-11
references.pmid: 21352257