@article{0ce2a5c2a1d24fca8fb5e726784f7dff,
title = "Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia",
abstract = "Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.",
author = "Johnson Ung and Tan, {Su Fern} and Fox, {Todd E.} and Shaw, {Jeremy J.P.} and Vass, {Luke R.} and Pedro Costa-Pinheiro and Garrett-Bakelman, {Francine E.} and Keng, {Michael K.} and Arati Sharma and Claxton, {David F.} and Levine, {Ross L.} and Tallman, {Martin S.} and Cabot, {Myles C.} and Mark Kester and Feith, {David J.} and Loughran, {Thomas P.}",
note = "Funding Information: Ceramide nanoliposomal technology (CNL) has been licensed by Penn State Research Foundation to Keystone Nano, Inc. (PA, USA) and MK is Chief Technical Officer and co-founder of Keystone Nano and TPL is a member of the Scientific Advisory Board of Keystone Nano. MK has co-founded other technology companies (Oraceu, TX, PA, USA; AgroSpheres Inc., VA, USA; Transfoam, Inc., VA, USA) that do not have access to any Kester sphingolipid-based technologies. TPL is on the Scientific Advisory Board and has stock options for Bioniz Therapeutics and Dren Bio, Inc. TPL and DJF received honoraria from Kymera Therapeutics. DJF has research funding from AstraZeneca. DC is participating in clinical studies of leukemia therapeutics funded by Aptose Biosciences, Astellas Pharma, AbbVie, Daiichi-Sankyo. MST is on the advisory board of AbbVie, Daiichi-Sankyo, Orsenix, KAHR Medical, Oncolyze, Jazz Pharmaceuticals, Roche, Biosight, Novartis, Kura, Innate Pharmaceuticals, Syros Pharmaceuticals, and Ipsen Biopharmaceuticals; has received clinical research funding from AbbVie, Glycomimetics, Amgen, Rafael Pharmaceuticals, Orsenix, and BioSight; and has received royalties from UpToDate. RLL is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, BAKX Therapeutics, Zentalis Pharmaceuticals, Ajax, Auron Therapeutics, Prelude Therapeutics, C4 Therapeutics and IsoPlexis. RLL has received research support from AbbVie , Constellation, Ajax, Zentalis Pharmaceuticals, and Prelude Therapeutics. RLL has received research support from and consulted for Celgene and Roche and has consulted for Syndax Pharmaceuticals, Incyte Corporation, Janssen Pharmaceuticals , Astellas Pharma , MorphoSys AG , and Novartis. RLL has received honoraria from AstraZeneca and Novartis for invited lectures and from Gilead Sciences and Novartis for grant reviews. There are no conflicts of interest with the work presented in this manuscript. Funding Information: This work was supported by the National Institutes of Health under the National Cancer Institute Award Number P01CA171983 (to TPL and MK), under the National Cancer Institute Research Training Award Number 5T32CA009109-45 (to JU), and under the National Cancer Institute Individual Predoctoral to Postdoctoral Fellow Transition Award Number 5K00CA245802 (to PCP). DC is supported by National Cancer Institute Award Number U10CA180820 . Studies supported by MSK core facilities were supported in part by MSKCC Support Grant/Core Grant P30 CA008748 and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Ceramide nanoliposomal technology (CNL) has been licensed by Penn State Research Foundation to Keystone Nano, Inc. (PA, USA) and MK is Chief Technical Officer and co-founder of Keystone Nano and TPL is a member of the Scientific Advisory Board of Keystone Nano. MK has co-founded other technology companies (Oraceu, TX, PA, USA; AgroSpheres Inc., VA, USA; Transfoam, Inc., VA, USA) that do not have access to any Kester sphingolipid-based technologies. TPL is on the Scientific Advisory Board and has stock options for Bioniz Therapeutics and Dren Bio, Inc. TPL and DJF received honoraria from Kymera Therapeutics. DJF has research funding from AstraZeneca. DC is participating in clinical studies of leukemia therapeutics funded by Aptose Biosciences, Astellas Pharma, AbbVie, Daiichi-Sankyo. MST is on the advisory board of AbbVie, Daiichi-Sankyo, Orsenix, KAHR Medical, Oncolyze, Jazz Pharmaceuticals, Roche, Biosight, Novartis, Kura, Innate Pharmaceuticals, Syros Pharmaceuticals, and Ipsen Biopharmaceuticals; has received clinical research funding from AbbVie, Glycomimetics, Amgen, Rafael Pharmaceuticals, Orsenix, and BioSight; and has received royalties from UpToDate. RLL is on the supervisory board of Qiagen and is a scientific advisor to Imago, Mission Bio, BAKX Therapeutics, Zentalis Pharmaceuticals, Ajax, Auron Therapeutics, Prelude Therapeutics, C4 Therapeutics and IsoPlexis. RLL has received research support from AbbVie, Constellation, Ajax, Zentalis Pharmaceuticals, and Prelude Therapeutics. RLL has received research support from and consulted for Celgene and Roche and has consulted for Syndax Pharmaceuticals, Incyte Corporation, Janssen Pharmaceuticals, Astellas Pharma, MorphoSys AG, and Novartis. RLL has received honoraria from AstraZeneca and Novartis for invited lectures and from Gilead Sciences and Novartis for grant reviews. There are no conflicts of interest with the work presented in this manuscript.This work was supported by the National Institutes of Health under the National Cancer Institute Award Number P01CA171983 (to TPL and MK), under the National Cancer Institute Research Training Award Number 5T32CA009109-45 (to JU), and under the National Cancer Institute Individual Predoctoral to Postdoctoral Fellow Transition Award Number 5K00CA245802 (to PCP). DC is supported by National Cancer Institute Award Number U10CA180820. Studies supported by MSK core facilities were supported in part by MSKCC Support Grant/Core Grant P30 CA008748 and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = sep,
doi = "10.1016/j.blre.2022.100950",
language = "English (US)",
volume = "55",
journal = "Blood Reviews",
issn = "0268-960X",
publisher = "Churchill Livingstone",
}