MPD in Telomerase Null Mice

Abstract

Abstract : Recent work over the past year from our laboratory has forged an intimate link between a common age-associated hematopoietic disorder, MPD, and telomere dysfunction in aging telomere dysfunctional mTerc null mice. This finding is particularly notable because one might expect telomere dysfunctional mice to exhibit complete bone marrow failure, rather than the selective expansion and loss of particular hematopoietic lineages. Over the past year we have solidified our initial observations, which include an age- and telomere dysfunction associated peripheral blood red cell anemia, neutrophilia, and thrombocythemia. These alterations were accompanied by substantial increases in plasma erythropoietin and several inflammatory cytokines, notably IL-6. These alterations in peripheral blood were accompanied by substantial changes elsewhere in the hematopoietic system. In the spleen we noted extensive extramedullary hematopoiesis and splenomegaly, and subsequent loss of lymphoid follicles and replacement by granulocytic lineages. Finally, in the bone marrow, we noted hypercellular bone marrows primarily made up of developing granulocytic lineages with a corresponding loss of developing erythroid and lymphoid lineages. In total, these phenotypes are reminiscent of myeloproliferative disorders (MPDs) that increase in incidence in elderly humans, and thus telomere dysfunctional mTerc null mice may represent a good model system to understand these age-related pathologies. We have initiated quantification and purification of hematopoietic stem cells (HSC) from these mutant mice and also initiated short term transplantation experiments.