Inhibition of Sphingosine Kinase 1 can lead to MCL1-dependent cell death in AML

Survival of Acute Myeloid Leukemia (AML) patients remains poor despite improvements in therapeutic strategies. Sphingosine Kinase 1 (SPHK1) is an oncogenic lipid kinase that converts sphingosine to Sphingosine-1-Phosphate (SIP). SIP plays a crucial role in promoting cell survival, proliferation, and chemotherapy resistance in a variety of hematological malignancies. Elevated levels of SPHK1 have been shown to be associated with AML¹. The mechanism of action and efficacy of SPHK1 in primary AML have not been elucidated hence the rationale for the study reported below.

In an article published in Blood, Jason A. Powell from the University of South Australia and the University of Adelaide, Australia, and colleagues investigated the role and the effect of targeting SPHK1 in primary AML patient cells².

The key results of the study were:

• Compared to normal Hematopoietic Stem Cells (HSCs), mean SPHK1 mRNA expression was significantly higher in all cytogenetic subclasses of AML cells
• SPHK1 mRNA expression was six-fold higher in primary AML patient samples (n = 171) compared to Normal Bone Marrow (NBM) samples; P < 0.05
• SPHK1a and SPHK1c were expressed in the Mononuclear Cells (MNCs) of AML patient samples (n = 13) but not in NBM MNCs
• AML patient samples were sensitive to MP-A08, a SPHK1 inhibitor, with an IC50 ranging from 6.4 to 18.9 µM
• CD34+ NBM progenitors were resistant to MP-A08
• Overexpression of SPHK1 led to enhanced chemotherapeutic resistance to cytarabine
• Upon treatment with MP-A08, significant reduction of leukemic burden was reported in mice engrafted with primary AML patient xenografts, AML 1 and AML10; P = 0.02
• Event Free Survival (EFS) in MP-A08 treated mice and vehicle treated mice; 99 vs 57 days, P = 0.005
• Upon treatment of AML cell lines with MP-A08, there was a significant decrease in the levels of MCL1, a pro-survival protein, upon treatment with MP-A08
• Treatment of AML cell lines increases pro-apoptotic proteins BIM, NOXA, and cleaved BID
• Combination of MP-A08 and ABT-737 (targets other pro-survival proteins but not MCL1) induced synergistic death in AML cells
• Inhibition of SIP Surface Receptor 2 (SIPR2) with JTE-013, reduced MCL1 expression
• ABT-737 combined with JTE-013 induced synergistic cell death in AML cells

In summary, inhibition of SPHK1 in human AML cells can lead to an induction of MCL1 degradation and caspase dependent cell death in AML cells.

The authors concluded by suggesting that targeting SPHK1 to block MCL1 expression may be an effective therapeutic strategy in AML. They also suggested that a combinational therapy of ABT-737 and agents that target SPHK1/SIPR2 may be effective in the treatment of AML. Finally, they propose that targeting survival pathways may overcome the diverse molecular landscape associated with AML.

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34+ progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient–derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML.