Citations

Abstract Multiple myeloma (MM) is a malignancy of plasma B-cells that is invariably preceded by monoclonal gammopathy of undetermined significance (MGUS), a pre-neoplastic plasma cell proliferative disorder. C57Bl/KaLwRij (KaLwRij) is a spontaneous inbred mouse strain predisposed to benign idiopathic paraproteinemia (BIP), a plasma cell dyscrasia that parallels many features of human pathology including progression to myeloma. In both humans and mice, the genetic basis for MGUS/MM risk is unknown. We sought to identify the genetic basis for MGUS/MM risk in KaLwRij mice to shed light on genes or pathways that mediate disease risk in humans. Using an integrative approach, we combined KaLwRij x B6 haplotype analysis (418 genes) and a MM patient association study (180 genes) to identify five candidate genes likely to contribute to both murine BIP-susceptibility and human MM risk. Surprisingly, we found KaLwRij mice had homozygous germline deletion of one of the five candidate genes, Samsn1, a putative negative regulator of B-cell activation. Consistent with the reported inhibitory function of SAMSN1 in B-cells, KaLwRij mice had enhanced naïve B-cell response in vitro following stimulation with IL4 and LPS and in vivo following immunization. We found that re-expression of Samsn1 in KaLwRij-derived myeloma cell line 5TGM1 decreased MM tumor growth in vitro, suggesting that loss of Samsn1 contributes to tumor growth in part through a cell intrinsic mechanism. Importantly, germline risk alleles may also influence cell types beyond the pre-malignant B-cells. It is established that the host environment also plays a critical role in supporting myeloma growth in KaLwRij mice. We found that Samsn1 is highly expressed in macrophages, but not in other MM-supportive cell types including osteoclasts and bone marrow stromal cells. Myeloma-associated macrophages play critical roles in supporting tumor growth and are broadly classified as anti-tumor M1 macrophages and tumor-promoting M2 macrophages. Microarray analysis of macrophages from B6 and KaLwRij mice prior to onset of BIP revealed three differentially expressed genes, but only one, Samsn1, is conserved in the human genome. We found that both unpolararized primary peritoneal and MCSF cultured bone marrow macrophages from healthy KaLwRij mice had markedly elevated expression of pro-tumorigenic M2 macrophage markers FIZZ1 and YM1 compared to B6 controls, despite the absence of activating cytokines. To confirm that loss of Samsn1 influenced macrophage activation and M2 polarization, we obtained bone marrow macrophages from mice with a targeted deletion of Samsn1 and found that unpolarized Samsn1-/- cells had similarly increased pro-tumor M2 macrophage marker expression. To evaluate the biologic significance of Samsn1 loss in macrophages on MM tumor growth, we established 5TGM1 MM tumors and injected M2 polarized macrophages from B6, KaLwRij, or Samsn1-/- mice. We found that MM tumor burden was markedly enhanced by the addition of a Samsn1-/- or KaLwRij macrophages compared to wild type macrophages. Thus, we found that loss of Samsn1 in macrophages enhances M2 polarization, prior to MGUS/MM development and can promote established myeloma tumor growth. Together, this data suggests that Samsn1 is a gene contributing to BIP-susceptibility in KaLwRij mice through mutually exclusive functions in multiple cell types including B-cells and macrophages. It is likely that SAMSN1 and its pathway members contribute to human MM progression, and may represent a point for preventative therapeutic intervention. Disclosures No relevant conflicts of interest to declare.

Background Minnesota has an ethnically diverse labor force, with the largest number of refugees per capita in the United States. In recent years, Minnesota has been and continues to be a major site for immigrant and refugee resettlement in the United States, with a large population of both immigrant and native born Hmong, Hispanic, and East Africans. This study seeks to evaluate the injury risk among the evolving minority workforce in the Minnesota Twin Cities region. Methods A retrospective cohort study identifying work‐related injuries following pre‐employment examinations was performed using electronic health records from a large multi‐clinic occupational medicine practice. Preplacement examinations and subsequent work‐related injuries were pulled from the electronic health record using representative ICD‐10 codes for surveillance examinations and injuries. This study included patient records collected over a 2‐year period from January 1, 2015, through December, 2016. The patients in this cohort worked in a wide‐array of occupations including production, assembly, construction, law enforcement, among others. Results Hispanic minority workers were twice as likely to be injured at work compared with White workers. Hispanics were 2.89 times more likely to develop back injuries compared with non‐Hispanic workers, and 1.86 times more likely to develop upper extremity injuries involving the hand, wrist, or elbow. Conclusion Clinical practice data shows that Hispanic workers are at increased risk for work‐related injuries in Minnesota. They were especially susceptible to back and upper extremity injuries. Lower injury rates in non‐Hispanic minority workers, may be the result of injury underreporting and require further investigation.