  Mathematical modeling offers the opportunity to test hypothesis concerning
Myeloproliferative emergence and development. We tested different mathematical
models based on a training cohort (n=264 patients) (Registre de la c\^ote d'Or)
to determine the emergence and evolution times before JAK2V617F classical
Myeloproliferative disorders (respectively Polycythemia Vera and Essential
Thrombocytemia) are diagnosed. We dissected the time before diagnosis as two
main periods: the time from embryonic development for the JAK2V617F mutation to
occur, not disappear and enter in proliferation, and a second time
corresponding to the expansion of the clonal population until diagnosis. We
demonstrate using progressively complexified models that the rate of active
mutation occurrence is not constant and doesn't just rely on individual
variability, but rather increases with age and takes a median time of 63.1+/-13
years. A contrario, the expansion time can be considered as constant: 8.8 years
once the mutation has emerged. Results were validated in an external cohort
(national FIMBANK Cohort, n=1248 patients). Analyzing JAK2V617F Essential
Thrombocytema versus Polycythemia Vera, we noticed that the first period of
time (rate of active homozygous mutation occurrence) for PV takes
approximatively 1.5 years more than for ET to develop when the expansion time
was quasi-similar. In conclusion, our multi-step approach and the ultimate
time-dependent model of MPN emergence and development demonstrates that the
emergence of a JAK2V617F mutation should be linked to an aging mechanism, and
indicates a 8-9 years period of time to develop a full MPN.
