Intratibial Injection of Human Multiple Myeloma Cells in NOD/SCID IL-2Rγ(Null) Mice Mimics Human Myeloma and Serves as a Valuable Tool for the Development of Anticancer Strategies

Abstract

BackgroundWe systematically analyzed multiple myeloma (MM) cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents.Design and MethodsUsing flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null) mice (NSG).ResultsMyeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID). Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses.ConclusionsOur results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

“…Thus, we exploited tibial intramedullary injection to develop an orthotopic PDX model using a sample of a relapsed patient pretreated with various drugs, including bortezomib (the patient's background is provided in ). Engraftment was confirmed by detecting human immunoglobulins in the serum of mice, as carried out at the clinical bedside . Serum levels of human immunoglobulins were measured monthly to evaluate tumor progression or therapeutic effects (Figure A).…”

“…Engraftment was confirmed by detecting human immunoglobulins in the serum of mice, as carried out at the clinical bedside. 40,41 Serum levels of human immunoglobulins were measured monthly to evaluate tumor progression or therapeutic effects ( Figure 7A).…”

The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1-Fluoro-2-(Imidazo-[1,2-α]Pyridin-3-yl)-Ethyl-Bisphosphonate)

“…The proportion of bone marrow occupied by the myeloma cells was assessed using OsteoMeasure and expressed as a percentage of the whole bone section area as described . Tumor burden was also assessed in bone marrow flushes of the left femora by flow cytometry using an anti‐human HLA‐ABC‐APC antibody and an isotype‐matched control (R&D Systems, Minneapolis, MN, USA) as described …”

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

“…Given this, in conjunction with the MM cellular hierarchy and the BM EMN recommendations on the treatment of newly diagnosed MM haematologica | 2014; 99 (2) 239 © F e r r a t a S t o r t i F o u n d a t i o n microenvironment being altered during tumor progression, this makes targeting of both an attractive approach, and fuels the ongoing pursuit of in vitro assays and murine models as crucial steps forward. [89][90][91][92] That clinical drug resistance is linked to interconvertible phenotypic and functional states of tumor-propagating cells has been described for MM subpopulations, where post-germinal pre-PCs are more quiescent, enriched in epigenetic regulators and 300-fold more drug-resistant than mature PCs, suggesting that these might be responsible for MRD, drug-resistant relapse and require development of alternative therapeutic strategies. 93 Understanding genetic events in MM also involves clarification of the genetic predisposition of MGUS and MM.…”