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KOS 2007: A transgenic mouse model that faithfully reproduces the pathogenesis, biology and clinical features of multiple myeloma
Marta Chesi, MD
Comprehensive Cancer Center
Mayo Clinic Arizona
Scottsdale, AZ, USA
06.26.07



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AUTHORS: M. Chesi, M. Sebag, S. Haas, S. Palmer, A.K. Stewart, P.L. Bergsagel
Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ, USA

SUMMARY:
By Lynne Lederman, PhD

Important features of human myeloma, to recapitulate in an animal model include indolent disease with fully differentiated plasma cells, monoclonal antibody production to levels greater than 35 g/L that are easily detectable in serum, somatic hypermutation of Ig genes, class switch recombination (because human IgM myelomas are rare), and end organ damage. Although there are no perfect models, the V kappa myc transgenic mouse model (Vk*MYC) of myeloma has many of these desirable features. Myc was chosen for the construct because it is typically dysregulated in post germinal center malignancies (including Burkitt lymphoma and myeloma), and in this system is activated only in germinal centers. By 50 weeks these transgenic mice have more than 10% plasma cells in their bone marrow (CD138+ B220 neg), and develop stable gammopathies at 70 weeks (38.6 g/L IgG; wild type mice have 2.8 g/L). The proliferative index of the plasma cells is low, and they are found only in the bone marrow. End organ damage includes anemia, protein deposits in the kidneys, and lytic bone lesions visible by x-ray. Occasionally hind limb paralysis due to spinal compression occurs. Bone mineral density is assessable by micro CT. The myeloma has an indolent course with median survival of 2 years (661 days, vs. 954 days for wild type mice). Proof of principle for drug testing has been established, with drug efficacy paralleling activity in human myeloma. Class switch occurs in most animals, as does somatic hypermutation. When these mice are crossed with mice expressing Bcl2 which provides additional survival signals, the disease becomes very aggressive and plasma cells disrupt both spleen and lymph nodes. Dr. Chesi’s group would like to study chromosomal abnormalities in this model by GEP, and they are making these mice available for further drug testing.


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