The malignant transformation of hematopoietic stem cells (HSCs) is a multi-step process. In myeloproliferative neoplasms (MPNs), the JAK2 V617F missense mutation is found in most patients and loss of function TET2 mutations co-occur in approximately 10% of patients. Despite comprehensive genomic profiling, disease heterogeneity exists amongst individuals which cannot be solely resolved by genetic approaches. The microenvironment surrounding HSCs can be diverse and dynamic and deregulated cytokine levels have been implicated in the development of myeloid malignancies. One molecule in particular, IP-10/CXCL10, correlated strongly with disease severity and with JAK2 / TET2 mutational status with highest levels present in the serum of double-mutant patients and in JAK2/TET2 double-mutant mouse models compared to wild-type controls and to other MPN mouse models (e.g., CALRdel52) which recapitulate the MPN phenotype. To test the potential functional role of IP-10 in disease development and maintenance, we generated an allelic series of mutant mouse models carrying mutations in the JAK2, TET2 and IP10 genes. In transplantation experiments, JAK2/TET2 double mutant cells were slowed in their ability to drive an MPN in IP-10-/- animals, but eventually developed a strong disease phenotype, suggesting that the mutant clone itself eventually begins to produce IP-10. In double-mutant JAK2V617F/ V617F IP-10-/- models and triple mutant JAK2V617F/ V617F TET2-/- IP-10-/-, partial amelioration of disease phenotype in some animals as measured by serial monitoring of peripheral blood hemoglobin and hematocrit levels as well as erythroid differentiation assays. Together, these studies suggest that IP-10 may play a role in disease modulation at the red cell progenitor stage and set the stage for future studies exploring its reduction as a potential therapeutic modality in MPNs. The malignant transformation of hematopoietic stem cells (HSCs) is a multi-step process. In myeloproliferative neoplasms (MPNs), the JAK2 V617F missense mutation is found in most patients and loss of function TET2 mutations co-occur in approximately 10% of patients. Despite comprehensive genomic profiling, disease heterogeneity exists amongst individuals which cannot be solely resolved by genetic approaches. The microenvironment surrounding HSCs can be diverse and dynamic and deregulated cytokine levels have been implicated in the development of myeloid malignancies. One molecule in particular, IP-10/CXCL10, correlated strongly with disease severity and with JAK2 / TET2 mutational status with highest levels present in the serum of double-mutant patients and in JAK2/TET2 double-mutant mouse models compared to wild-type controls and to other MPN mouse models (e.g., CALRdel52) which recapitulate the MPN phenotype. To test the potential functional role of IP-10 in disease development and maintenance, we generated an allelic series of mutant mouse models carrying mutations in the JAK2, TET2 and IP10 genes. In transplantation experiments, JAK2/TET2 double mutant cells were slowed in their ability to drive an MPN in IP-10-/- animals, but eventually developed a strong disease phenotype, suggesting that the mutant clone itself eventually begins to produce IP-10. In double-mutant JAK2V617F/ V617F IP-10-/- models and triple mutant JAK2V617F/ V617F TET2-/- IP-10-/-, partial amelioration of disease phenotype in some animals as measured by serial monitoring of peripheral blood hemoglobin and hematocrit levels as well as erythroid differentiation assays. Together, these studies suggest that IP-10 may play a role in disease modulation at the red cell progenitor stage and set the stage for future studies exploring its reduction as a potential therapeutic modality in MPNs.