Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes.

Acute myeloid leukemia (AML) is an aggressive disease with complex and heterogeneous biology. Although several genomic classifications have been proposed, there is a growing interest in going beyond genomics to stratify AML. In this study, we profile the sphingolipid family of bioactive molecules in 213 primary AML samples and 30 common human AML cell lines. Using an integrative approach, we identify two distinct sphingolipid subtypes in AML characterized by a reciprocal abundance of hexosylceramide (Hex) and sphingomyelin (SM) species. The two Hex-SM clusters organize diverse samples more robustly than known AML driver mutations and are coupled to latent transcriptional states. Using transcriptomic data, we develop a machine-learning classifier to infer the Hex-SM status of AML cases in TCGA and BeatAML clinical repositories. The analyses show that the sphingolipid subtype with deficient Hex and abundant SM is enriched for leukemic stemness transcriptional programs and comprises an unappreciated high-risk subgroup with poor clinical outcomes. Our sphingolipid-focused examination of AML identifies patients least likely to benefit from standard of care and raises the possibility that sphingolipidomic interventions could switch the subtype of AML patients who otherwise lack targetable alternatives.
Competing Interests: Conflict of Interest Disclosures: ADV is a scientific advisor to Arima Genomics. BMB is the owner/founder of Tahosa Bio, LLC (Rapid City, SD). MST has received research funding from AbbVie, Orsenix, BioSight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; on the advisory boards for AbbVie, Daiichi-Sankyo, Orsenix, KAHR, Oncolyze, Jazz Pharma, Roche, BioSight, Novartis, Innate Pharma, Kura, Syros Pharmaceuticals, Ipsen Biopharmaceuticals, Cellularity; has received royalties from UpToDate (for writing); is Chair for Data and Safety Monitoring Board (DSMB) for HOVON 156; is Chair of Adjudication Committee for Foghorn Therapeutics; has received honoraria from Northwell Health, Japan Society of Hematology, MetroHealth Cleveland, Ohio State University, American Society of Hematology; is on Board for American Society of Hematology. RLL is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, and Isoplexis. He receives research support from Ajax and Zentalis and has consulted for Incyte, Janssen, Astra Zeneca, and Novartis. He has received honoraria from Astra Zeneca, Roche, Lilly, and Amgen for invited lectures and from Gilead for grant reviews. DJF has received research funding, honoraria, and/or stock options from AstraZeneca, Dren Bio, Recludix Pharma, and Kymera Therapeutics. KAJ serves on the Scientific Advisory Board of BridgeBio. TPL has received Scientific Advisory Board membership, consultancy fees, honoria, and/or stock options from Keystone Nano, Flagship Labs 86, Dren Bio, Recludix Pharma, Kymera Therapeutics, and Prime Genomics. There are no conflicts of interest with the work presented in this manuscript. Other authors declare no competing interests.