INFLAMMATION OF THE VASCULAR NICHE ENHANCES LEUKEMIA-INITIATING CELL METABOLIC SWITCH

Acute myeloid leukemia (AML) alters the normal bone marrow (BM) vascular architecture, although several clinical trials testing vasculature-specific agents showed modest efficacy. These findings suggest that a deeper understanding of BM endothelial cell (EC)-specific pathways providing a pre-malignant/pro-tumoral niche is imperative to efficiently target angiogenesis and vascular integration. We previously generated tamoxifen-inducible transgenic mice with constitutively activated MAPK signaling in BM ECs (MAPKVCC), which displayed profound decline in HSC and progenitor potential, loss of vascular integrity and enhanced inflammation. We observed that MAPK pathway activation conferred BMECs the ability to significantly expand putative MLL-AF9 AML leukemia-initiating cells (LIC) in our ex vivo platform. Moreover, transplantation of LICs first expanded on MAPKVCC BMECs resulted in notably shorter survival of recipient mice, compared to mice receiving control BMEC-expanded LICs. MAPKVCC BMECs displayed increased glycolytic capacity at steady state and under stress conditions by Seahorse assays, as well as high respiratory capacity. MAPKVCC BMECs induced a metabolic switch in MLL-AF9 LICs ex vivo, towards increased glycolysis in both steady and stressed state and retained oxidative respiration potential under stress. We observed increased extracellular lactate levels over time in MAPKVCC BMEC single cultures as well as higher lactate levels in presence of AML, consistently with their hyperglycolytic metabolic profiles. Moreover, upregulated expression of MCT4 and MCT1, the monocarboxylate transporters mediating lactate efflux and lactate uptake, respectively, in both MAPKVCC BMECs and cKit+ AML cells ex vivo suggests the existence of a lactate shuttle, coupling BMEC-AML metabolic needs, that might support the emergence of LICs at the expenses of normal hematopoiesis.