Survival of patients with acute myelogenous leukemia (AML) depends on our ability to prevent relapse in patients that achieved complete remission after intensive chemotherapy. While studies focusing on the malignant clone brought many advances in understanding AML biology and chemoresistance, little improvement has been made in eliminating the last bastion of malignant cells, the minimal residual disease (MRD). Inspired by Sir Paget's "soil and seed" hypothesis, it is becoming more clear that there is constant feedback between the malignant clone and the leukemic microenvironment. This "molecular conversation" dictates AML behavior and holds the key to eliminating MRD. Here we review recent advances in our understanding of how leukemia cells modify their microenvironment and how these changes reinforce AML homeostasis. In addition, we outline current clinical and preclinical efforts to disrupt these interactions and to therapeutically target MRD.
