Elevated Lactate in Acute Myeloid Leukemia Bone Marrow Microenvironment Dysfunction, with a Dual Role of GPR81 in Macrophage Polarization and Leukemia Cell Growth

Abstract

ABSTRACTInteractions between acute myeloid leukemia (AML) and the hematopoietic bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. We measured elevated extracellular metabolites in the BMME of AML patients, including lactate. Lactate has been implicated in solid tumors for inducing suppressive tumor-associated macrophages, and correlates with poor prognosis. We describe a role of lactate in the polarization of leukemia-associated macrophages (LAMs), using a murine model of blast crisis chronic myelogenous leukemia (bcCML). Elevated lactate also diminished the function of hematopoietic progenitors and stromal supportin vitro. Mice genetically lacking the lactate receptor GPR81 were used to demonstrate lactate-GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. We report microenvironmental lactate as a critical driver of AML-induced BMME dysfunction and leukemic progression, thus identifying GPR81 as an exciting and novel therapeutic target for the treatment of this devastating disease.