title: Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow.
abstract: Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.
authors.affiliation: Division of Hematology, University Hospitals, Geneva, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Matthes
authors.affiliation: Department of Pathology, Medicine Faculty, Geneva, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: McKee
authors.affiliation: Department of Pathology-Immunology, Medicine Faculty, Geneva, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Analytical Immunology of Chronic Pathologies, INSERMU823/University Joseph Fourier, Albert Bonniot Institute, La Tronche, France.
authors.forename: B
authors.initials: B
authors.lastname: Manfroi
authors.affiliation: Hematology, University Hospital, Grenoble, France.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.affiliation: Hematology, University Hospital, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Passweg
authors.affiliation: Division of Hematology, University Hospitals, Geneva, Switzerland.|Analytical Immunology of Chronic Pathologies, INSERMU823/University Joseph Fourier, Albert Bonniot Institute, La Tronche, France.
authors.forename: B
authors.initials: B
authors.lastname: Huard
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D038042:Myelopoiesis / Q000235:genetics; D019899:Paracrine Communication; D011485:Protein Binding; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053300:Tumor Necrosis Factor Ligand Superfamily Member 13