A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma.
Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (3-D) culture model of reconstructed bone marrow (BM, n = 48) and mobilized blood autografts (n = 14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model, melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal com-partment. Bortezomib targeted only CD138(+)CD56(+) MM plasma cells. The localization of nonproliferating cells to the reconstructed endosteum, in contact with N-cadherin-positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20(+) cells were enriched more than 10-fold by melphalan treatment, exhibited self-renewal, and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex vivo MM cells. The 3-D culture provides a novel biologically relevant preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells.
Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, AB, Canada.
Julia
J
Kirshner
Kyle J
KJ
Thulien
Lorri D
LD
Martin
Carina
C
Debes Marun
Tony
T
Reiman
Andrew R
AR
Belch
Linda M
LM
Pilarski
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D002869:Chromosome Aberrations; D002999:Clone Cells; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D008954:Models, Biological; D009101:Multiple Myeloma / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan