Long-term Hematopoietic Transfer of the Anti-Cancer and Lifespan-Extending Capabilities of A Genetically Engineered Blood System by Transplantation of Bone Marrow Mononuclear Cells

Abstract

AbstractA causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termedEklfK74R/K74RorEklf(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics including cancer resistance. We show that the healthy longevity characteristics of theEklf(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age- and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property ofEklf(K74R) mice could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at young age of the latter. Furthermore, NK(K74R) cells carry higherin vitrocancer cell-killing ability than wild type NK cells. Targeted/global gene expression profiling analysis has identified changes of the expression of specific proteins, including the immune checkpoint factors PD-1 and PD-L1, and cellular pathways in the leukocytes of theEklf(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/ blood system for long-term anti-cancer and, potentially, for anti-aging.