Myeloid Malignancies and the Marrow Microenvironment: Some Recent Studies in Patients with MDS

There is growing evidence for a role of the hemopoietic microenvironment in the pathophysiology of myelodysplastic syndromes (MDS). Effects of various cytokines on the marrow microenvironment of patients with MDS have been studied. Autoimmunity, i.e. a reaction of autologous T lymphocytes against components of the marrow is also operative in a proportion of patients with MDS. The negative feed-back loop that controls tumor necrosis factor (TNF)α levels in healthy individuals is apparently disrupted in MDS due to auto-amplification signals involving TNFα and interleukin (IL-32). IL-32 mRNA levels in primary adherent cells from patients with MDS are 14- to 17-fold higher than in controls. In contrast, cells from patients with chronic myelomonocytic leukemia (CMML), a myeloproliferative disorder with low TNFα levels, express IL-32 at only 1/10 the level observed in controls. Damage in the microenvironment may occur secondary to oxidative stress, which may also lead to accelerated shortening of telomeres. This is, indeed, true for hematopoietic cells in MDS marrow, but telomere length in marrow stroma does not differ from that in age-matched healthy individuals. Nevertheless, the stroma shows functional aberrancies. Stroma-derived signals facilitate apoptosis in clonal hematopoietic cells but not in normal CD34+ cells. Thus while stroma dysfunction is likely due to signals derived from the hematopoietic clone rather than being intrinsic, it does affect clonal death or survival, respectively. Therefore, signals exchanged between both compartments could serve as targets for therapeutic interventions.