Summary
Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knock-down of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation.
Encephalitozoon cuniculi caused chronic nonlethal infections in euthymic BALB/cAnN mice, whereas athymic BALB/cAnN-nu mice died from infection. Specific, anamnestic, transferable, and acquired responses against E. cuniculi were expressed by infected euthymic mice. Resistance to lethal disease appears to be T-cell dependent. Immune serum failed to protect infected athymic mice, whereas the transfer of T-enriched spleen cells from E. cuniculi-sensitized euthymic donors prevented lethal E. cuniculi infections in athymic mice. These findings indicate that murine encephalitozoonosis may be an excellent system for studies of a chronic infection in an immunologically well-characterized host.
Selected inbred strains of mice were examined for susceptibility to peritoneal infections with Encephalitozoon cuniculi. Marked differences in susceptibility and resistance among mouse strains were not controlled by loci within the mouse major histocompatibility (H-2) complex, but resistance in BALB/c mice was influenced by a dominant gene(s) outside the H-2 complex. The lethality of peritoneal infections in hypothymic nude mice suggested that resistance to encephalitozoonosis is dependent on thymus-derived lymphocytes. Peritoneal infection with E. cuniculi was associated with slightly enhanced proliferative spleen cell responses to mitogens in BALB/c mice and significantly depressed responses in C57Bl/6 mice. Infection in BALB/c mice was accompanied by normal antibody responses to sheep erythrocyte immunogens, but C57Bl/6 mice had depressed antibody responses. The results indicate that the immune system plays a major role in determining the course of peritoneal infections with E. cuniculi and that encephalitozoonosis can modulate the host's immune system.
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