Multiple Myeloma Studied in New Mouse Model Developed at Yale

Understanding how multiple myeloma develops and responds to therapies may be easier using a new mouse model developed at Yale University School of Medicine. The model supports the growth of cells derived from patients with multiple myeloma or the disease’s precursor states.

The study, “Microenvironment-Dependent Growth Of Preneoplastic And Malignant Plasma Cells In Humanized Mice,” published in Nature Medicine, may also help tackle cancer prevention in the future.

Most cases of multiple myeloma (MM) are preceded by the clinically asymptomatic precursor states of either monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM). Although several animal models were previously created to study the transformation of those conditions into malignant myeloma, past models lacked the genetic players that promote human MM and MGUS, which greatly limited studies.

“There is an unmet need for in vivo mouse models that would allow the growth and investigation of patient-specific primary human tumors (and particularly precursor states),” Yale professors Madhav Dhodapkar and Richard Flavell and other co-authors wrote in the study.

To overcome the obstacles, the team genetically modified mice to carry the human versions of six genes that participate in the development and growth of MM cells — M-CSF; IL-3; GM-CSF; thrombopoietin; SIRPα; and IL-6.

In the humanized mice animals, tumor growth was essentially restricted to the bone marrow. Because it is consistent with what happens in human patients with myeloma, it shows that the mice can be hosts for several blood diseases, from MGUS to plasma cell leukemia (PCL). The result offered several advantages over previously used models, particularly for the growth of precursor states.

Researchers observed that the tumors repeated the genomic diversity of the human MM type, which demonstrated that the new approach can be suitable for studying several blood disorders that can become cancer in humans and provide a way to understand the functional and biological differences of the tumors.

“Use of this humanized mouse model for the study of the biology of [MM] and emerging therapeutic approaches, as well as for the clinical evaluation of affected patients, may help the understanding the functional diversity of human tumors and the development of personalized therapies,” the authors wrote in the study report.