Cellular response to TPO depends on MPL/JAK2 expression. A model for normal and pathological megakaryopoiesis regulation by JAK2 and MPL expression levels. (A) The cell line model: TPO-induced cellular response depends on MPL/JAK2 protein expression in the UT7-MPL cell line model. A decrease in the expression of MPL at the cell surface can be induced by a decrease in either MPL (UT7-11oc2) or JAK2 (UT7-11oc3-7 and UT7-11oc1 shJAK2) protein expression. (B) We propose that during normal megakaryopoiesis, MPL/JAK2 expression could reach a threshold at which the signal induced by TPO switches from proliferation to cell-cycle arrest and terminal maturation. According to this model, each event inducing a decrease in JAK2 or MPL expression/signaling could extend the proliferative stage of megakaryopoiesis, resulting in an amplification of the progenitor cells’ compartment. This mechanism could be complementary, with the autonomous signaling in immature cells induced by mutations such as JAK2^V617F or MPL^W515 mutations. The situation that could occur in MPNs is shown (red lines).