Although the pathogenic role of STAT3 in human MPN still remains questionable, the contribution of STAT3 to TKI resistance elicited by the leukemic microenvironment would suggest that combination therapy or dual molecules targeting STAT3 and STAT5 might help to eradicate resistant leukemic cells in their “niche.” The gene discussed is STAT3; the disease is myeloproliferative neoplasm.