title: CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease.
abstract: Secreted protein CCN1, encoded by CYR61, is involved in wound healing, angiogenesis, and osteoblast differentiation. We identified CCN1 as a microenvironmental factor produced by mesenchymal cells and overexpressed in bones of a subset of patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (AMM), and multiple myeloma (MM). Our analysis showed that overexpression of CYR61 was independently associated with superior overall survival of MM patients enrolled in our Total Therapy 3 protocol. Moreover, elevated CCN1 was associated with a longer time for MGUS/AMM to progress to overt MM. During remission from MM, high levels of CCN1 were associated with superior progression-free and overall survival and stratified patients with molecularly defined high-risk MM. Recombinant CCN1 directly inhibited in vitro growth of MM cells, and overexpression of CYR61 in MM cells reduced tumor growth and prevented bone destruction in vivo in severe combined immunodeficiency-hu mice. Signaling through αvβ3 was required for CCN1 prevention of bone disease. CYR61 expression may signify early perturbation of the microenvironment before conversion to overt MM and may be a compensatory mechanism to control MM progression. Therapeutics that upregulate CYR61 should be investigated for treating MM bone disease.
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Sarah K
authors: SK
authors: Johnson
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: James P
authors: JP
authors: Stewart
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Rakesh
authors: R
authors: Bam
authors: Cancer Research and Biostatistics, Seattle, WA; and.
authors: Pingping
authors: P
authors: Qu
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Bart
authors: B
authors: Barlogie
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Frits
authors: F
authors: van Rhee
authors: Signal Genetics, LLC, New York, NY.
authors: John D
authors: JD
authors: Shaughnessy
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Joshua
authors: J
authors: Epstein
authors: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR;
authors: Shmuel
authors: S
authors: Yaccoby
mesh_terms: D000818:Animals; D058070:Asymptomatic Diseases; D001706:Biopsy; D001847:Bone Diseases / Q000209:etiology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D051379:Mice; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D055515:Cysteine-Rich Protein 61