All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.

The Multiple Myeloma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your Multiple Myeloma Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.
2017-03-18T13:41:25.000Z

Humanized mouse model for the study of MM

Mar 18, 2017
Share:

Bookmark this article

A new humanized mouse model has been developed by a team of researchers at Yale University, in order to study Multiple Myeloma (MM) in-vivo. Rituparna Das, along with Professors Richard A. Flavell and Madhav V. Dhodapkar, published their findings in Nature Medicine in November 2016. Notably, this model enables growth of pre-neoplastic plasma cells as well as malignant cells, and therefore also allows study of the precursor disease state of monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic MM (AMM). The authors found that both xenografts from patients with MM or cells from the precursor state were supported in this mouse model, signifying a strong role for extrinsic cues from the microenvironment.

Key Highlights

  • Mice (Rag2-deficient and IL-2Rϒ-deficient) were genetically engineered to carry human versions of six genes important for innate immune cell and myeloma cell development: IL-6; M-CSF; IL-3/GM-CSF; hSIRPα; TPO (thrombopoeitin); such mice were termed MIS(KI)TRG6

Growth of Human IL6-dependent cells:

  • INA-6 cells (human IL-6 dependent MM cell line) injected into the bones of mice expressing human IL-6 led to IL-6 dependent tumor growth, increased soluble IL-6 and bone destruction
  • Human IL-6 (hIL-6), but not mouse IL-6, supported growth of INA-6 and resultant bone destruction in vivo
  • INA-6 cells also grew in mice expressing hIL-6 and hSIRPα 

Growth of primary MM cells:

  • Primary MM cells isolated from bone marrow of patients and injected into the bones of MIS(KI)TRG6 mice grew within the bone, but not in the spleen; non-malignant cells were detected in the spleen as well
  • Injection of both CD138+ cells or a CD138-depleted cell population of bone marrow mononuclear cells (BMMNCs) into MIS(KI)TRG6 mice, led to the growth of CD138+ tumor cells in-vivo, indicating that both compartments can re-populate tumors
  • Residual non-tumor cells (T-cells, myeloid cells, NK cells and B cells) also underwent expansion in these mice

Microenvironment-dependent growth of MM and precursor states:

  • Injection of CD3-depleted BMMNCs from patients with either MGUS or AMM into MIS(KI)TRG6 mice led to the growth of tumor cells in-vivo, primarily within the bone
  • Samples from relapsed and refractory patients showed enhanced ability to grow in the contralateral bone; extramedullary growth was observed with more aggressive plasma cell leukemia (PCL)
  • Percentage of clonal plasma cells in xenograft from pts with pre-neoplastic gammopathy were higher than in the primary samples: 4.9% vs 27.4% (p=0.06)
  • The reliable growth of pre-neoplastic stages is a strong advantage of this model over the SCID-hu mice and other existing MM models

Genomic Diversity of Xenografts:

  • To test whether MM cells grown in the MIS(KI)TRG6 mouse retain the clonal diversity of the parental tumors, DNA from sort-purified tumor cells were analyzed by whole exome sequencing and compared to the parental cells
  • Loss of heterozygosity (LOH) patterns were retained from the parental tumors to the xenograft, although additional LOH changes were observed
  • Somatic copy number alterations (CNA) revealed a similar pattern, and both LOH and CNA changes were identical in individual mice transplanted with the same parental tumor 

In conclusion, the advantage of MIS(KI)TRG6 mice over other MM models is the ability to support growth of primary tumor cells, in both pre-neoplastic and more advanced malignant states, in-vivo. In addition, growth of tumor cells is largely restricted to the bone marrow, which is consistent with human MM. Ultimately, this mouse model will enable detailed studies of MM biology and development from early precursor states, as well as pre-clinical testing and the development of personalized therapies.  

Abstract

Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.

  1. Das R. et al. Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nat Med. 2016 Nov;22(11):1351-1357. DOI: 10.1038/nm.4202. Epub 2016 Oct 10.
More about...

Newsletter

Subscribe to get the best content related to multiple myeloma delivered to your inbox