Search

A large number of patients with advanced lymphoma become refractory or relapse after initial treatment due to the persistence of minimal residual disease. Ideal immunotherapy strategy for eradicating the minimal residual disease of lymphoma and preventing the tendency to relapse need to be developed. Here, we use a mice model mimicked the disease entities of aggressive B-cell lymphoma dynamically to analyze the host anti-lymphoma immunity during the progression of lymphoma. We have shown that STAT3 activity was gradually enhanced in host immune effector cells with the progression of lymphoma. Inhibition of the STAT3 activity with a small molecule inhibitor was able to effectively enhance the function of both host innate and adaptive immunity, and thereby delayed the progression of lymphoma. Despite the therapeutic benefits were achieved by using of the STAT3 inhibitor, disrupting of STAT3 pathway did not prevent the eventual development of lymphoma due to the presence of point mutation of β2M, which controls immune recognition by T cells. Our findings highlight the complexity of the mechanism of immune evasion; therefore a detailed analysis of genes involved in the immune recognition process should be essential before an elegant immunotherapy strategy could be conducted.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, and primary drug resistance and relapse are thought to be the main causes for treatment failure in ALL patients. For these refractory or relapsed patients, there is an increasing demand to identify novel therapeutic approaches, which will highly rely on the use of xenotransplantation models in translational research. Given the critical role that the spleen plays in the hematopoiesis and lymphopoiesis in adult mice, intrasplenic inoculation of ALL cells into immunodeficient mice may represent a feasible route for leukemic xenotransplantation. In the present study, engraftments via intrasplenic inoculation in anti-mCD122 mAb conditioned NOD/SCID mice were achieved in 5 out of 11 cases, and the engrafted cells reconstituted a complete leukemic phenotype. The engrafted cells sustained the self-renewal capacity of leukemia-initiating cells as tested by serial xenotransplantation and can be used for evaluation of antileukemic drugs. These data suggest that the combination of intrasplenic inoculation and the targeted depletion of CD122(+) cells could provide a novel approach for the xenotransplantation of ALL cells in NOD/SCID mice. Furthermore, this model can be used for stem cell research, long-term analysis of engraftment kinetics and in vivo drug tests.

The Stress-responsive activator of p300 (Strap) is a transcription co-factor that has an important role in the control of DNA damage response through its ability to regulate p53 activity. Recent studies have however suggested that Strap takes on a wider role in regulating the cellular response to stress. Thus, Strap is now known to be inducible by heat shock and stimulate the transcription of heat-shock genes. A chromatin-associated complex involving heat-shock factor 1 (HSF1), Strap and the p300 co-activator assembles on the HSP70 gene promoter, and Strap augments HSF1 binding and chromatin acetylation in HSP genes, most probably through recruiting p300 acetyltransferase. Cells depleted of Strap do not survive under heat-shock conditions. It appears therefore that Strap is an essential co-factor that acts at the level of chromatin control to regulate heat-shock-responsive transcription. These recent studies underscore the central role taken on by transcription co-factors in integrating and co-ordinating different cellular stress response pathways.