Challenges

To understand normal regulation of proliferation and cell death mechanisms in B-lymphoid cells is instrumental in order to understand development of lymphoid malignancies and immune deficiency syndromes and to reveal targets for improved treatments of such diseases.

Of particular interest is our finding that proliferation and survival of memory B cells stimulated via toll like receptor 9 (TLR-9) and RP105 (CD180) is enhanced by vitamin A. Since TLR-9 signaling in B cells is compromised in immune disorders like common variable immune disorder (CVID), our long term goal is to use our knowledge to improve treatment of these diseases. We have already demonstrated that the vitamin A metabolite retinoic acid (RA) can improve vital defects in B cells from CVID patients, and we have also revealed the ability of RA to protect CVID-derived B cells to DNA damage as a mean to reduce the increased cancer incidence in these patients. We are now addressing the role of RA in regulating the balance between autophagy and reactive oxygen species (ROS) in normal B cells and B cells from CVID patients.

One of the important cellular barriers against developing cancer is the tumor suppressor p53, and it is generally assumed that p53 must be inactivated in order for cancer to develop. We have shown that cAMP-signaling prevents DNA damage-induced p53 and cell death in B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells but not in normal B cell precursors, suggesting that cAMP-signaling might be a driving force in development of BCP-ALL. We have addressed the role of  bone marrow stromal cells to provide BCP-ALLs with cAMP-activating signals like prostaglandine 2 (PGE2), and to use inhibitors of PGE2 formation and inhibitors of cAMP-signaling to improve treatment of BCP-ALL. We have established a xenograft model of ALL in NSG mice, and we use In vivo imaging to follow the development of leukemia in these mice. In our current projects, we study how cAMP signaling regulates the interplay between ROS, autophagy and survival of ALL cells in culture and in our animal model, and we are now also linking these events to metabolic changes in the cells. 

Published Mar. 7, 2011 11:04 AM - Last modified Jan. 6, 2022 1:26 PM