Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice.
Zainul Shoyeb HasanaliAlfred L GarfallLisa BurzenskiLeonard D ShultzYan TangSiddhant KaduNeil C SheppardDerek DopkinDan T VoglAdam David CohenAdam J WaxmanSandra P Susanibar-AdaniyaMartin P CarrollEdward A StadtmauerDavid AllmanPublished in: bioRxiv : the preprint server for biology (2024)
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.
Keyphrases
- multiple myeloma
- single cell
- induced apoptosis
- newly diagnosed
- cell cycle arrest
- endothelial cells
- cell therapy
- rna seq
- high fat diet induced
- signaling pathway
- cell death
- chronic kidney disease
- body composition
- high throughput
- endoplasmic reticulum stress
- risk factors
- bone marrow
- ejection fraction
- acute lymphoblastic leukemia
- metabolic syndrome
- cell proliferation
- acute myeloid leukemia
- insulin resistance
- mesenchymal stem cells
- high density
- induced pluripotent stem cells
- adipose tissue
- postmenopausal women
- patient reported outcomes