Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia

Aijun Liao, Kathleen Broeg, Todd Fox, Su Fern Tan, Rebecca Watters, Mithun Vinod Shah, Lucy Q. Zhang, Yongping Li, Lindsay Ryland, Jun Yang, Cesar Aliaga, Alden Dewey, Andrew Rogers, Kelly Loughran, Leah Hirsch, Nancy Ruth Jarbadan, Kendall Thomas Baab, Jiangang (Jason) Liao, Hong-Gang Wang, Mark Kester & 4 others Dhimant Desai, Shantu Amin, Thomas P. Loughran, Xin Liu

Research output: Contribution to journalArticle

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Abstract

NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.

Original languageEnglish (US)
Pages (from-to)2793-2800
Number of pages8
JournalBlood
Volume118
Issue number10
DOIs
StatePublished - Sep 8 2011

Fingerprint

Natural Killer Cells
Rats
Leukemia
Apoptosis
Degradation
Sphingolipids
Sphingosine
Therapeutics
Caspases
Metabolism
Reactive Oxygen Species
Large Granular Lymphocytic Leukemia
Cells
Fingolimod Hydrochloride
Inbred F344 Rats
Cell Line
Survival

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Liao, A., Broeg, K., Fox, T., Tan, S. F., Watters, R., Shah, M. V., ... Liu, X. (2011). Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia. Blood, 118(10), 2793-2800. https://doi.org/10.1182/blood-2011-01-331447
Liao, Aijun ; Broeg, Kathleen ; Fox, Todd ; Tan, Su Fern ; Watters, Rebecca ; Shah, Mithun Vinod ; Zhang, Lucy Q. ; Li, Yongping ; Ryland, Lindsay ; Yang, Jun ; Aliaga, Cesar ; Dewey, Alden ; Rogers, Andrew ; Loughran, Kelly ; Hirsch, Leah ; Jarbadan, Nancy Ruth ; Baab, Kendall Thomas ; Liao, Jiangang (Jason) ; Wang, Hong-Gang ; Kester, Mark ; Desai, Dhimant ; Amin, Shantu ; Loughran, Thomas P. ; Liu, Xin. / Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia. In: Blood. 2011 ; Vol. 118, No. 10. pp. 2793-2800.
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abstract = "NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.",
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Liao, A, Broeg, K, Fox, T, Tan, SF, Watters, R, Shah, MV, Zhang, LQ, Li, Y, Ryland, L, Yang, J, Aliaga, C, Dewey, A, Rogers, A, Loughran, K, Hirsch, L, Jarbadan, NR, Baab, KT, Liao, JJ, Wang, H-G, Kester, M, Desai, D, Amin, S, Loughran, TP & Liu, X 2011, 'Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia', Blood, vol. 118, no. 10, pp. 2793-2800. https://doi.org/10.1182/blood-2011-01-331447

Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia. / Liao, Aijun; Broeg, Kathleen; Fox, Todd; Tan, Su Fern; Watters, Rebecca; Shah, Mithun Vinod; Zhang, Lucy Q.; Li, Yongping; Ryland, Lindsay; Yang, Jun; Aliaga, Cesar; Dewey, Alden; Rogers, Andrew; Loughran, Kelly; Hirsch, Leah; Jarbadan, Nancy Ruth; Baab, Kendall Thomas; Liao, Jiangang (Jason); Wang, Hong-Gang; Kester, Mark; Desai, Dhimant; Amin, Shantu; Loughran, Thomas P.; Liu, Xin.

In: Blood, Vol. 118, No. 10, 08.09.2011, p. 2793-2800.

Research output: Contribution to journalArticle

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T1 - Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia

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AU - Broeg, Kathleen

AU - Fox, Todd

AU - Tan, Su Fern

AU - Watters, Rebecca

AU - Shah, Mithun Vinod

AU - Zhang, Lucy Q.

AU - Li, Yongping

AU - Ryland, Lindsay

AU - Yang, Jun

AU - Aliaga, Cesar

AU - Dewey, Alden

AU - Rogers, Andrew

AU - Loughran, Kelly

AU - Hirsch, Leah

AU - Jarbadan, Nancy Ruth

AU - Baab, Kendall Thomas

AU - Liao, Jiangang (Jason)

AU - Wang, Hong-Gang

AU - Kester, Mark

AU - Desai, Dhimant

AU - Amin, Shantu

AU - Loughran, Thomas P.

AU - Liu, Xin

PY - 2011/9/8

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N2 - NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.

AB - NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.

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Liao A, Broeg K, Fox T, Tan SF, Watters R, Shah MV et al. Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia. Blood. 2011 Sep 8;118(10):2793-2800. https://doi.org/10.1182/blood-2011-01-331447