Physiology of myeloproliferation

The current dogma about polycythemia vera (PV) is that one or more genetic mutations in a hematopoietic stem cell (HSC) cause abnormal proliferation and differentiation of the progeny of that stem cell. This model ignores two fundamental characteristics of biologic systems that must be considered if regulation is to be understood: first, at a molecular level, biochemical processes are intrinsically stochastic; and second, ontogeny and hematopoiesis are branching processes-with one cell dividing into two cells, and so on. Why is it important to add an understanding of the stochastic, branching nature of HSC function to a description of the genes and gene products only? Why not just say one understands the regulation of normal hematopoiesis, or PV, when all the genes and gene products actively transcribed have been identified? The answer is that within a branching, stochastic process, one mutation can cause more than one outcome (phenotype) in the future. There will be one or more related outcomes that will be highly likely and others that will be less likely. Although most patients will have similar phenotypes, some will differ, but not because they have different underlying mutations. Mathematics will probably play an increasingly important role in describing and analyzing the regulation that occurs as the genetic program of HSC is expressed within a clone over time. Semin Hematol 38(suppl 2):5-9.