Acute myeloid leukemia stratifies as 2 clinically relevant sphingolipidomic subtypes

Abstract

Acute myeloid leukemia (AML) is an aggressive, heterogeneous disease with genomic subtypes that are increasingly treated differently. There is a growing interest in going beyond mutations and cytogenetics to stratify AML. Recent work has combined proteomics,1 signaling,2,3 or immunophenotypes4 with integrated genomic-transcriptomic measurements to improve AML risk classifications.5 Although invaluable as resources, such approaches can neither extend retroactively to existing repositories nor prospectively to new AML cases lacking these data types. We sought to develop a more extensible approach involving sphingolipids (Figure 1A), a family of bioactive molecules implicated in AML pathogenesis and therapeutic resistance6,7 that differentially regulate cell proliferation,8 differentiation,9 autophagy,10 apoptosis,11 and immune cell activation.12 Sphingolipid abundances in AML vary heterogeneously and ratiometrically,13 prompting us to ask whether systematic sphingolipidomic profiling could meaningfully stratify patients with AML and common AML cell lines.