Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice

Hasanali, Z. S.; Garfall, A.; Burzenski, L.; Shultz, L.; Tang, Y.; Kadu, S.; Sheppard, N.; Dopkin, D.; Vogl, D. T.; Cohen, A. D.; Waxman, A. J.; Susanibar-Adaniya, S.; Carroll, M.; Stadtmauer, E.; Allman, D. M.

doi:10.1101/2024.01.21.576547

bioRxiv · 10.1101/2024.01.21.576547

Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice

Hasanali, Z. S.·Garfall, A.·Burzenski, L.·Shultz, L.·Tang, Y.·Kadu, S.·Sheppard, N.·Dopkin, D.·Vogl, D. T.·Cohen, A. D.·Waxman, A. J.·Susanibar-Adaniya, S.·Carroll, M.·Stadtmauer, E.·Allman, D. M.

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Abstract

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

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Hasanali, Z. S., Garfall, A., Burzenski, L., Shultz, L., Tang, Y., Kadu, S., Sheppard, N., Dopkin, D., Vogl, D. T., Cohen, A. D., Waxman, A. J., Susanibar-Adaniya, S., Carroll, M., Stadtmauer, E., Allman, D. M.. 2024-01-24. Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice. https://doi.org/10.1101/2024.01.21.576547

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