Figure 3. Tracking the cell-of-origin in cases with co-incident MPN mutations.

The pattern of co-existent JAK2 and MPL mutations apparent in some MPN cases could arise in several ways. In Model A, JAK2V617F-positive and MPLW515L-positive colony-forming cells would result from secondary mutations acquired separately in cells of a common founder clone. As the likelihood of co-incident mutations occurring by chance is significantly less than the observed frequency, the shared founder clone would have to carry a mutation in unknown gene(s), Z, that increases the likelihood of subsequent mutation or promotes the survival of mutant JAK2- or MPL-positive cells. In Model B, the JAK2V617F and MPLW515L mutations occur separately in independent hematopoietic stem cells. Experimental proof for the latter possibility is obtained by evaluating in informative female patients expression from loci undergoing X-inactivation. In Model A, with allele C on the imprinted X chromosome (shaded in black), all mutation-positive cells express the “T” transcript. An identical pattern would occur in half of those cases in which Model B was operative: by chance, the JAK2 and MPL mutations were acquired in unrelated stem cells that both had an active T allele (“1st possibility”). However, in the remaining 50% (“2nd possibility”), one mutation would occur in a stem cell expressing “T”, the other in a stem cell expressing “C”.