Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

Jason A Powell, Alexander C. Lewis, Wenying Zhu, John Toubia, Melissa R. Pitman, Craig T. Wallington-Beddoe, Paul A B Moretti, Diana Iarossi, Saumya E. Samaraweera, Nik Cummings, Hayley S Ramshaw, Daniel Thomas, Andrew H. Wei, Angel F Lopez, Richard J D'Andrea, Ian D. Lewis, Stuart M Pitson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, 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 primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient 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.

Original languageEnglish
Pages (from-to)771-782
Number of pages12
JournalBlood
Volume129
Issue number6
DOIs
Publication statusPublished - 9 Feb 2017

Cite this

Powell, J. A., Lewis, A. C., Zhu, W., Toubia, J., Pitman, M. R., Wallington-Beddoe, C. T., ... Pitson, S. M. (2017). Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood, 129(6), 771-782. https://doi.org/10.1182/blood-2016-06-720433
Powell, Jason A ; Lewis, Alexander C. ; Zhu, Wenying ; Toubia, John ; Pitman, Melissa R. ; Wallington-Beddoe, Craig T. ; Moretti, Paul A B ; Iarossi, Diana ; Samaraweera, Saumya E. ; Cummings, Nik ; Ramshaw, Hayley S ; Thomas, Daniel ; Wei, Andrew H. ; Lopez, Angel F ; D'Andrea, Richard J ; Lewis, Ian D. ; Pitson, Stuart M. / Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. In: Blood. 2017 ; Vol. 129, No. 6. pp. 771-782.
@article{e57f19707f8b4481966e6227e6d4d04e,
title = "Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia",
abstract = "Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, 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 primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient 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.",
author = "Powell, {Jason A} and Lewis, {Alexander C.} and Wenying Zhu and John Toubia and Pitman, {Melissa R.} and Wallington-Beddoe, {Craig T.} and Moretti, {Paul A B} and Diana Iarossi and Samaraweera, {Saumya E.} and Nik Cummings and Ramshaw, {Hayley S} and Daniel Thomas and Wei, {Andrew H.} and Lopez, {Angel F} and D'Andrea, {Richard J} and Lewis, {Ian D.} and Pitson, {Stuart M}",
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Powell, JA, Lewis, AC, Zhu, W, Toubia, J, Pitman, MR, Wallington-Beddoe, CT, Moretti, PAB, Iarossi, D, Samaraweera, SE, Cummings, N, Ramshaw, HS, Thomas, D, Wei, AH, Lopez, AF, D'Andrea, RJ, Lewis, ID & Pitson, SM 2017, 'Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia', Blood, vol. 129, no. 6, pp. 771-782. https://doi.org/10.1182/blood-2016-06-720433

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. / Powell, Jason A; Lewis, Alexander C.; Zhu, Wenying; Toubia, John; Pitman, Melissa R.; Wallington-Beddoe, Craig T.; Moretti, Paul A B; Iarossi, Diana; Samaraweera, Saumya E.; Cummings, Nik; Ramshaw, Hayley S; Thomas, Daniel; Wei, Andrew H.; Lopez, Angel F; D'Andrea, Richard J; Lewis, Ian D.; Pitson, Stuart M.

In: Blood, Vol. 129, No. 6, 09.02.2017, p. 771-782.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

AU - Powell, Jason A

AU - Lewis, Alexander C.

AU - Zhu, Wenying

AU - Toubia, John

AU - Pitman, Melissa R.

AU - Wallington-Beddoe, Craig T.

AU - Moretti, Paul A B

AU - Iarossi, Diana

AU - Samaraweera, Saumya E.

AU - Cummings, Nik

AU - Ramshaw, Hayley S

AU - Thomas, Daniel

AU - Wei, Andrew H.

AU - Lopez, Angel F

AU - D'Andrea, Richard J

AU - Lewis, Ian D.

AU - Pitson, Stuart M

PY - 2017/2/9

Y1 - 2017/2/9

N2 - Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, 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 primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient 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.

AB - Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, 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 primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient 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.

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Powell JA, Lewis AC, Zhu W, Toubia J, Pitman MR, Wallington-Beddoe CT et al. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood. 2017 Feb 9;129(6):771-782. https://doi.org/10.1182/blood-2016-06-720433