IL-15 and HDAC inhibitors in leukemia

Role of Interleukin-15 in the histone deacetylase inhibitor modulation of MHC class I associated chain in leukemic cells

Project director: Mihnea Zdrenghea, MD, PhD
Postdoc Grant: UEFISCDI PN-II-RU-PD-2011-3-0277
Starting date: november 2011
Duration: 1 year

Project Summary

Acute leukemias are hematologic malignancies with dismal prognosis; current treatment is of limited efficacy and new therapies are urgently warranted. Histone deacetylase inhibitors (HDACi) have recently emerged as agents with potent anticancer activity, effective in hematological malignancies including myeloid leukemias. Several agents are currently under investigation. An important mechanism attributed to their anticancer effect is up-regulation by HDACi of surface molecules in malignant cells, such as MHC class I-associated chains A and B (MICA and B), which act as ligands for the NKG2D receptor on natural killer and CD8+ T cells, increasing their non-specific cytotoxic activity towards malignant cells. Interleukin-15 (IL-15), a promising agent under investigation in cancer, was shown to modulate MICA/B in several cell types. Our hypothesis is that the anticancer effect of HDACi is occurring, at least in part, through IL-15 and IL-15Rα.modulation. Our aim is to investigate modulation of MIC in leukemic cells by HDACi, modulation of IL-15 by HDACi and the role of IL-15 in MIC molecules modulation by HDACi., starting with in vitro studies on leukemic cell lines, followed by ex vivo studies using leukemic cells from our biobank. Increasing knowledge concerning the mechanisms of beneficial effects of HDACi in leukemia will help development of new therapies. Additionally, we may find biomarkers useful in the selection and monitoring of patients treated with these agents.

Publications:

M.T. Zdrenghea, Could interleukin-15 potentiate histone deacetylase inhibitor effects in haematological malignancy?, Med Hypotheses. 2013 Aug;81(2):311-5. doi: 10.1016/j.mehy.2013.04.021. Epub 2013 May 10.
http://www.medical-hypotheses.com/article/S0306-9877(13)00191-6/abstract