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.

Keywords: Bcl-2; Ceramide; Mcl-1; Sphingolipid dysregulation; Sphingosine-1-phosphate; Therapeutics.

Figure 1.. Transit map of sphingolipid metabolism.

Ceramides reside at the canonical center of the sphingolipid metabolism transit map and serve as the central hub for the other sphingolipids. De novo synthesis begins with the condensation of serine and palmitoyl-CoA by the serine palmitoyltransferase (SPT) complex and further processing by 3-ketodihydrosphingosine reductase (KDSR), dihydroceramide synthases (CERS1–6), and dihydroceramide desaturases (DEGS1–2) to generate ceramide (D train). Other methods of generating ceramides include sphingomyelin hydrolysis (S train) by sphingomyelin phosphodiesterases (SMPD1–4) or CERS activity as part of the exit/salvage pathway (E train). Conversely, there are multiple routes to decrease cellular ceramide content. The addition of a phosphocholine head group by the sphingomyelin synthase enzymes (SGMS1–2) generates sphingomyelin (S train). Ceramidases (ASAH1–2 and ACER1–3) hydrolyze ceramide into sphingosine and free fatty acids, and sphingosine kinases (SPHK1–2) phosphorylate sphingosine into sphingosine-1-phosphate (E train). S1P breakdown by sphingosine-1-phosphate lyase (SGPL1) generates phosphoethanolamine and hexadecenal. Ceramide kinase (CERK) phosphorylates ceramide to generate ceramide-1-phosphate (P train). The synthesis of complex glycosphingolipids begins with the action of galactosylceramide synthase (UGT8) to generate galactosylceramides (G train north) or glucosylceramide synthase (UGCG) to generate glucosylceramides (G train south).

Figure 2.. Summary of dysregulated sphingolipid signaling in AML.

The intersections between dysregulated sphingolipid metabolism and oncogenic signaling in AML are many. Multiple ceramide catabolizing enzymes (AC, SPHK, ACER3) are elevated in de novo AML. Multidrug resistance also upregulates the metabolite C1P and the enzymes AC, SPHK, GCS, and SMS. Overexpression of AC, SPHK, or GCS is sufficient to induce upregulation of MDR1, likely through glycosphingolipids or S1P-mediated NF-κB signaling. Oncogenic FLT3-signaling inhibits ceramide generation by antagonizing CERS1. Overexpression of AC, ACER3, SPHK, and the S1P transporter SPNS2, correlate with poorer overall survival. Bcl-2 and Bcl-xL inhibit the formation of ceramide pores. Ceramides and S1P signaling regulate levels of the pro-survival Bcl-2 family protein, Mcl-1. In addition, S1P-S1PR signaling upregulates levels of phospho-Akt and phospho-ERK. Signaling through S1PR3 promotes myeloid differentiation. KDSR, involved in de novo SL synthesis, prevents ER stress to promote leukemic maintenance. Black arrows = metabolic pathway; green arrows = activating; red inhibitory arrow = inactivating; red text = overexpressed and/or oncogenic proteins.

Figure 3.. Dysregulated sphingolipid metabolism in AML and potential therapeutic intervention.

Refer to Figure 2 for a detailed summary of dysregulated sphingolipid metabolism in AML and Table 2 for a representative list of sphingolipid-modulating drugs that are FDA-approved or in clinical trials. In summary, multiple mechanisms contribute to ceramide depletion and S1P accumulation in AML, which are targeted by the indicated therapeutics. Dysregulated sphingolipid metabolites and enzymes are labeled in red. A larger node indicates upregulation of a particular metabolite. A large arrow indicates increased flux while a dashed arrow indicates decreased flux through a pathway. Clinically relevant compounds and their targets are labeled.