title: Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma.
abstract: Multiple myeloma is a malignant disorder characterized by bone marrow proliferation of plasma cells and by overproduction of monoclonal immunoglobulin detectable in the sera (M-spike). Anemia is a common complication of multiple myeloma, but the underlying pathophysiological mechanisms have not been completely elucidated. We aimed to identify the different determinants of anemia using the Vk*MYC mouse, which spontaneously develops an indolent bone marrow localized disease with aging. Affected Vk*MYC mice develop a mild normochromic normocytic anemia. We excluded the possibility that anemia results from defective erythropoietin production, inflammation or increased hepcidin expression. Mature erythroid precursors are reduced in Vk*MYC bone marrow compared with wild-type. Malignant plasma cells express the apoptogenic receptor Fas ligand and, accordingly, active caspase 8 is detected in maturing erythroblasts. Systemic iron homeostasis is not compromised in Vk*MYC animals, but high expression of the iron importer CD71 by bone marrow plasma cells and iron accumulation in bone marrow macrophages suggest that iron competition takes place in the local multiple myeloma microenvironment, which might contribute to anemia. In conclusion, the mild anemia of the Vk*MYC model is mainly related to the local effect of the bone marrow malignant clone in the absence of an overt inflammatory status. We suggest that this reproduces the initial events triggering anemia in patients.
authors.affiliation: Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bordini
authors.affiliation: Division of Molecular Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Maria Teresa Sabrina
authors.initials: MT
authors.lastname: Bertilaccio
authors.affiliation: Pathology and Myeloma Units, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Fermo
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic AZ, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic AZ, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy camaschella.clara@hsr.it.
authors.forename: Clara
authors.initials: C
authors.lastname: Camaschella
authors.affiliation: Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy Fondazione Centro San Raffaele, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Campanella
mesh_terms: D000740:Anemia / Q000097:blood* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007501:Iron / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000097:blood* / Q000235:genetics / Q000473:pathology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D007501:Iron