The myeloproliferative neoplasms (MPNs) are characterized by overproduction of mature blood cells and increased risk of transformation to frank leukemia. The acquired kinase mutation JAK2V617F plays a central role in a majority of patients with these diseases. As MPNs are clonal stem cell disorders (i.e. arise from a single stem cell which eventually expands), the hematopoietic stem/progenitor cell (HSPC) compartment in MPNs is heterogeneous with the presence of both JAK2 wild-type and JAK2V617F mutant cells. Mechanisms responsible for the mutant stem cell expansion in MPNs are not fully understood. Utilizing in vitro co-culture assays and in vivo competitive transplantation assays, we show that the presence of wild-type cells alters both the gene expression profile and cellular function of JAK2V617F mutant HSPCs and inhibits the expansion of co-existing JAK2V617F mutant cells in a normal microenvironment. In contrast, we found that a microenvironment bearing the mutant kinase promotes JAK2V617F mutant HSPC expansion over wild-type cells due in part to altered CXCL12/CXCR4 signaling. Further understanding of the molecular mechanisms controlling the competitive interactions between normal and JAK2V617F mutant cells, and how these mechanisms break down during MPN disease progression hold great potential for advances in treating patients with these diseases.