Model of the clonal progression in myeloproliferative disorder (MPD). The onset of MPD is preceded by a somatic mutation (sporadic MPD) or germ-line mutation (familial MPD) in an as yet unknown gene(s). The onset of MPD coincides with the acquisition of a mutation in JAK2 or other genes (gray box). Acute leukemia can arise de novo or from the MPD clone. Leukemic transformation of a “pre-JAK2” progenitor or stem cell could explain the absence of JAK2-V617F in leukemic blasts from MPD patients previously positive for JAK2-V617F. Alternatively, JAK2-V617F could be lost during mitotic recombination of a cell heterozygous for JAK2-V617F (dashed line).