Mathematical model and inferred dynamics of JAK2^V617F, CALR^m, and MPL^m cells. (A) Design of the mathematical model. Mature and fully differentiated cells no longer divide and die at a rate δ_m. We modeled progenitor cells as originating from active HSCs that divide and encounter several divisions (modeled by the parameter κ_i). Progenitors exit their compartment at the differentiation rate δ_i and proliferate (modeled by the parameter κ_m) before entering the mature compartment. We also introduced 2 stem cell compartments depending on whether the HSC is considered active or inactive (quiescent), parameters ɣ and β model the exchanges between these 2 compartments. We assumed that the active HSCs might be recruited to differentiate at a rate α to contribute to hematopoiesis. Parameter Δ models the propensity of the stem cell pool to be depleted (if Δ < 0) or to expand (if Δ > 0). (B) Examples of dynamics of inferred mutated progenitor, HSC (CF), and mutated mature cells (VAF) are presented. Dynamics focusing on (i) homozygous JAK2^V617F cells for 3 patients, (ii) heterozygous JAK2^V617F cells from 2 patients, (iii) heterozygous CALR^m cells from 2 patients, and (iv) heterozygous MPL^m cells from a patient. Dots, square, and triangles, experimental data values; curves, median values determined from the mathematical model; red line, inferred dynamics of mutated HSCs (overlaid with the heterozygous progenitor CF for CALR^m cases); shaded areas surrounding each curve, 95% confidence intervals. When comparing mature cells dynamics to heterozygous progenitor dynamics, we must keep in mind that the VAF in progenitor cells would be half the CF.