Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia

Ung, Johnson; Tan, Su‐Fern; Fox, Todd E.; Shaw, Jeremy J.P.; Vass, Luke R.; Costa-Pinheiro, Pedro; Garrett-Bakelman, Francine E.; Keng, Michael; Sharma, Aruna; Claxton, David F.; Levine, Ross L.; Tallman, Martin S.; Cabot, Myles C.; Kester, Mark; Feith, David J.

doi:10.1016/j.blre.2022.100950

Cited by 11 publications

(15 citation statements)

References 225 publications

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“…Future studies should confirm these findings and investigate the pharmacologic vulnerabilities of the two sphingolipid subtypes. Given the promise of targeting sphingolipid metabolism in AML 7,23,24 , we envision that sphingolipidomic subtyping could contribute to tailored treatment selections for AML patients that otherwise lack targetable alternatives.…”

Section: Resultsmentioning

confidence: 99%

“…Although invaluable as resources, such approaches cannot 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 resistance 6,7 . Sphingolipid species are delicately balanced and several differentially regulate cell proliferation 8 , differentiation 9 , autophagy 10 , apoptosis 11 , and immune cell activation 12 .…”

Section: Introductionmentioning

confidence: 99%

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Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Paudel

Tan

Fox

et al. 2023

Preprint

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Paudel

Tan

Fox

et al. 2023

Preprint

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“…Poly (ADP-ribose) polymerase-1 (PARP) cleavage is routinely used as a marker of caspase activation and was observed at 12 hours and 24 hours post LCL-805 treatment, with weaker cleavage detected in OCI-AML2 cells ( Figure 5A, B ). Sphingolipids are linked to Bcl-2 family proteins, gatekeepers of caspase-dependent apoptotic cell death [14], and the endogenous caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP) [33, 34]. LCL-805 treatment did not decrease protein levels of the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xL, or XIAP ( Figure 5A, B ).…”

Section: Resultsmentioning

confidence: 99%

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Ung,

Tan,

Fox

et al. 2023

Preprint

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

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“…As briefly mentioned, SLs have long been implicated in hematological malignancies. Thorough reviews on the roles of SLs in various hematological malignancies have been published previously [ 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ] and we strongly encourage all readers to peruse these to obtain a robust foundation for the updates we will be presenting herein.…”

Section: Introductionmentioning

confidence: 99%

Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies

Raza

Atallah²,

Luberto³

2022

IJMS

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Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.

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Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia

Cited by 11 publications

References 225 publications

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies

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