Characterization of the role of Samsn1 loss in multiple myeloma development

Abstract

The protein SAMSN1 was recently identified as a putative tumor suppressor in multiple myeloma, with re‐expression of Samsn1 in the 5TGM1/KaLwRij murine model of myeloma leading to a near complete abrogation of intramedullary tumor growth. Here, we sought to clarify the mechanism underlying this finding. Intratibial administration of 5TGM1 myeloma cells into KaLwRij mice revealed that Samsn1 had no effect on primary tumor growth, but that its expression significantly inhibited the metastasis of these primary tumors. Notably, neither in vitro nor in vivo migration was affected by Samsn1 expression. Both knocking‐out SAMSN1 in the RPMI‐8226 and JJN3 human myeloma cell lines, and retrovirally expressing SAMSN1 in the LP‐1 and OPM2 human myeloma cell lines had no effect on either cell proliferation or migration in vitro. Altering SAMSN1 expression in these human myeloma cells did not affect the capacity of the cells to establish either primary or metastatic intramedullary tumors when administered intratibially into immune deficient NSG mice. Unexpectedly, the tumor suppressive and anti‐metastatic activity of Samsn1 in 5TGM1 cells were not evidenced following cell administration either intratibially or intravenously to NSG mice. Crucially, the growth of Samsn1‐expressing 5TGM1 cells was limited in C57BL/6/Samsn1−/− mice but not in C57BL/6 Samsn1+/+ mice. We conclude that the reported potent in vivo tumor suppressor activity of Samsn1 can be attributed, in large part, to graft‐rejection from Samsn1−/− recipient mice. This has broad implications for the design and interpretation of experiments that utilize cancer cells and knockout mice that are mismatched for expression of specific proteins.

Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?

“…In contrast to these results, Dong et al performed a transplantation study of TCL1 leukemic cells into PI3Kd KI mice, which resulted in reduced TCL1 leukemia growth in comparison to WT recipient mice (147). Of importance, tumor cell transplantation in mice with genetic differences between the donor and recipient has been shown to cause tumor rejection in the TCL1 mouse model of CLL (150) as well as a model of multiple myeloma (151), which seems a likely explanation for the lower TCL1 tumor burden in PI3Kd KI versus WT mice. Rechallenge of these PI3Kd KI mice, which previously rejected TCL1-leukemia, with tumor cells resulted again in tumor rejection and expansion of CD44 + effector/memory CD4 + as well as CD8 + T-cells (147).…”

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts

“…As a tumor suppressor gene, the decreased expression of SAMSN1 was found in several cancers 45 . Additionally, low SAMSN1 protein production in hepatocellular carcinoma and gastric cancer was associated with decreased overall survival and expanded tumor size [45][46][47] . Thus, our results are in line with recent publications advocating that the levels of SAMSN1 protein can be associated with better immunotherapy response.…”