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Adoptive B-cell transfer mouse model of human myeloma

Leukemia volume 30, pages 962–966 (2016)Cite this article

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Our appreciation of the different molecular subtypes1 and the complex genomic architecture of myeloma2 has been recently enhanced by whole-exome and whole-genome DNA sequencing, indicating that myeloma cells typically harbor dozens of non-synonymous mutations.3, 4 Although myeloma is associated with recurrent mutations in a number of genes, including NRAS, KRAS, FAM46C, DIS3 and IRF4,3 there is no evidence for hallmark ‘unifying’ mutations that have been found in other blood cancers, such as BRAFV600E in hairy cell leukemia5 and MYD88L265P in Waldenström macroglobulinemia.6 The newly discovered myeloma alleles have raised the bar for preclinical mouse models of myeloma that can be used for interrogating pathways of tumor development and responses to new therapies. To rise to the challenge, more accurate, cost-effective and scalable models than what is currently available should be devised. In addition, next-generation mouse models of myeloma should be able to distinguish myeloma drivers from innocent bystander mutations, validate molecular targets for experimental myeloma interventions, elucidate mechanisms of acquired drug resistance and determine whether a myeloma gene operates in the tumor cells, the tumor microenvironment or both.

To evaluate the potential of BCL2+IL6+ B cells to give rise to myeloma-like tumors in genetically compatible hosts, B220+CD45.2+ splenocytes were obtained from BCL2+IL6+ mice and adoptively transferred, via retro-orbital IV injection, to CD45.1+ hosts pre-treated with a lethal dose of whole-body irradiation (Figure 1b, squares). Tumor development was fully penetrant (100% tumor incidence) and tumor onset was short (61 days median, 50–80 days range) in all B-cell-reconstituted mice (n=15). All tumors that arose from B cells that had been retrovirally transduced in vitro using a luciferase (Luc)-encoding cDNA gene exhibited strong reporter gene activity upon bioluminescence imaging in vivo (Figure 1c and Supplementary Figure 1). Disappointingly, however, serum paraproteins were not detected (Supplementary Figure 2A) and the tumors were classified as diffuse large B-cell lymphoma (DLBCL) based on histopathologic criteria (Supplementary Figure 2B).

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Acknowledgements

This work was supported in part by: NIH Hematology Training Grant T32 HL007344 to VST; NIH Pre-doctoral Training Grant T32 AI007485 to TRR; NCI Core Grant P30CA086862 in support of the Holden Comprehensive Cancer Center; Senior Research Awards from the Multiple Myeloma Research Foundation and International Waldenström’s Macroglobulinemia Foundation to SJ; and R01CA151354 from the NCI to SJ. C.CD45.1 congenic mice and the retroviral transduction system were kindly provided, respectively, by Drs Lyse A Norian and Dawn E Quelle (both UI). Special thanks to the UI Flow Cytometry, Central Microscopy Research and Comparative Pathology facilities for expert assistance.

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Authors and Affiliations

  1. Department of Pathology, University of Iowa (UI) Carver College of Medicine, Iowa City, IA, USA

    V S Tompkins, T R Rosean, C J Holman, C DeHoedt, A K Olivier, K M Duncan, X Jing, S D Foor & S Janz

  2. Department of Radiology, UI Carver College of Medicine, Iowa City, IA, USA

    M R Acevedo & S A Walsh

  3. Small Animal Imaging Core, UI Carver College of Medicine, Iowa City, IA, USA

    M R Acevedo & S A Walsh

  4. Department of Internal Medicine, UI Carver College of Medicine, Iowa City, IA, USA

    G Tricot & F Zhan

  5. Holden Comprehensive Cancer Center, UI Carver College of Medicine, Iowa City, IA, USA

    G Tricot, F Zhan & S Janz

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  1. V S Tompkins
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Correspondence to S Janz.

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Tompkins, V., Rosean, T., Holman, C. et al. Adoptive B-cell transfer mouse model of human myeloma. Leukemia 30, 962–966 (2016). https://doi.org/10.1038/leu.2015.197

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