Model for the regulation of HSC self-renewal and proliferation by TET2 loss, JAK2V617F, and the combination of JAK2V617F and TET2 loss. TET2 loss increases the self-renewal of HSCs without significant effects on their proliferation, explaining that TET2-deficient HSCs outcompete normal HSCs and lead to clonal hematopoiesis. The effects of JAK2V617F on HSCs are dependent on the level of expression and yet-unknown parameters. At low levels of expression, JAK2V617F induces the proliferation of HSCs but slightly decreases self-renewal. The proliferation effect being predominant, JAK2V617F HSCs are capable of outcompeting wild-type HSCs. At high levels of expression, JAK2V617F may more profoundly alter the functions of HSCs. The TET2 loss restores the function of JAK2V617F by increasing self-renewal. The restoration is complete or incomplete depending on the defect of the JAK2V617F HSCs. Overall, TET2 loss increases the fitness of JAK2V617F to induce an MPN.