Allman, D. M. | bioRxiv Science

bioRxiv2024

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

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.

cancer biology↗

bioRxiv2023

Parallel and divergent morphological adaptations underlying the evolution of jumping ability in ants

Jumping is a rapid locomotory mode widespread in terrestrial organisms. However, it is a rare specialization in ants. Forward jumping has been reported within four distantly related ant genera: Gigantiops, Harpegnathos, Myrmecia, and Odontomachus. The temporal engagement of legs/body parts during jump, however, varies across these genera. It is unknown what morphological adaptations underlie such behaviors, and whether jumping in ants is solely driven directly by muscle contraction or additionally relies on elastic recoil mechanism. We investigate the morphological adaptations for jumping behavior by comparing differences in the locomotory musculature between jumping and non-jumping relatives using x-ray micro- CT and 3D morphometrics. We found that the size-specific volumes of the trochanter depressor muscle (scm6) of the middle and hind legs are 3-5 times larger in jumping ants, and that one coxal remotor muscle (scm2) is reduced in volume in the middle and/or hind legs. Notably, the enlargement in the volume of other muscle groups is directly linked to the legs or body parts engaged during the jump. Furthermore, a direct comparison of the muscle architecture revealed two significant differences between in jumping versus non-jumping ants: First, the relative Physiological Cross-Sectional Area (PCSA) of the trochanter depressor muscles of all three legs were larger in jumping ants, except in the front legs of O. rixosus and M. nigrocincta; second, the relative muscle fiber length was shorter in jumping ants compared to non-jumping counterparts, except in the front legs of O. rixosus and M. nigrocincta. This suggests that the difference in relative muscle volume in jumping ants is largely invested in the area (PCSA), and not in fiber length. There was no clear difference in the pennation angle between jumping and non-jumping ants. However, the length of hind legs relative to body length was longer in jumping ants. Based on direct comparison of the observed vs. possible work and power output during jumps, we surmise that direct muscle contractions suffice to explain jumping performance, in two species, but elastic recoil is likely important in one. We suggest that increased investment in jumping-relevant musculature is a primary morphological adaptation that separates jumping from non-jumping ants. These results elucidate the common and idiosyncratic morphological changes underlying this rare adaptation in ants.

evolutionary biology↗