AML is a disease of impaired myeloid differentiation that is hierarchically organized like the normal blood system. Leukemia stem cells (LSCs) are resistant to standard chemotherapy and reconstitute the disease, leading to clinical relapse and often death. Inflammation has emerged as the linchpin in many human chronic conditions/diseases of aging including clonal hematopoiesis and atherosclerotic cardiovascular disease that directly or indirectly involve dysregulated myeloid cells. As abnormal lineage differentiation is a seminal property of many cancers including AML, uncovering novel lineage regulators could prove pivotal for developing successful therapeutic approaches involving differentiation induction (for example ATRA in acute promyelocytic leukemia). Understanding how hematopoietic stem cells (HSC) choose to differentiate into one lineage versus another has been a successful avenue for uncovering novel lineage regulators. Traditional studies have focused on the role of cytokines and the transcriptional factor networks that they engage. Although recent studies have uncovered metabolic properties as playing a major role in governing HSC fate including quiescence control, self-renewal, and survival properties, the role that variations in metabolic state play in lineage determination is less well understood.

Sphingosine-1-phosphate (S1P) is an obligate ligand for a family of five G-protein coupled receptors (S1PR1-5) known to play pleiotropic roles in cellular proliferation, survival, and migration; processes that are all dysregulated in inflammatory diseases including many cancers. We recently showed sphingolipid composition is diverse across the human hematopoietic hierarchy and uncovered a novel role for sphingolipid metabolism in determining human HSC fate (Xie, et al., Cell Stem Cell 2019). However, the role of S1P signaling in the interplay between normal hematopoiesis, AML and inflammation is not understood. Investigation of this axis led us to the novel discovery that signaling via this pro-inflammatory lipid through its receptor S1PR3 is a key process for myeloid lineage differentiation in human HSC that is dysregulated in AML (Xie, et al., submitted). S1PR3 induces a myeloid inflammatory program in HSCs. S1P-S1PR3 signaling distinguishes AMLs with a mature myeloid phenotype and common inflammatory signature. Functional studies involving modulation of this axis, including with the S1P prodrug FTY720, in LSCs induced differentiation and reduced engraftment ability, pointing to a novel therapeutic approach in AML. S1P modulators are currently used to treat multiple sclerosis and could be rapidly repurposed for treatment of AML. Development of a S1PR3-specific agonist could prove a promising avenue for differentiation therapy in a subset of LSCs.