The broad long term objective of this proposal is to understand the pathogenesis of natural killer (NK) LGL leukemia. The mechanisms responsible for expansion of leukemic NK cells are not completely known. Leukemic NK cells are characterized by Fas-resistance. Data supported by this grant has indicated that constitutively active RAS/MEK/ERK MAPK signaling contributes to the survival of leukemic NK cells. The central hypothesis of this proposal is that sphingolipid signaling as an upstream activator of RAS/MEK/ERK MAPK mediates leukemic NK cell survival. Our overall strategy will utilize a genetic approach to inhibit key pathway components in the specific aim. We anticipate that targeting these signaling cascades will reverse Fas-resistance in vitro and have therapeutic efficacy in an in vivo model of NK-LGL leukemia. Preliminary data indicate that many of the core genes central to sphingolipid metabolism such as acid ceramidase 1 (AC1) and sphingosine kinase 1(SPHK1) are differentially overexpressed in leukemic NK cells. We will test the hypothesis that alterations of ceramide/S1P rheostat contribute to Fas-resistance (Specific Aim). Pharmacological inhibition of either AC or SPHK1 led to apoptosis in leukemic NK cells. We found that S1P and dihydro-S1P levels were elevated in NK-LGL patients'sera. Furthermore, S1P protected leukemic NK cells from Fas-mediated apoptosis. AC and SPHK1 will be further evaluated as potential therapeutic targets of sphingolipid metabolism. Compelling preliminary data indicate that these key survival pathways are also activated in normal NK cells by target binding in vitro. Mechanistic investigations as outlined in this proposal will identify novel therapeutic targets for NK-LGL leukemia and also provide insight into survival mechanisms utilized by an activated innate immune system.

Public Health Relevance

This study is investigating leukemia which arises from killer cells of the immune system. The purpose of these studies is to understand the signals which keep the leukemia cells alive. This information can be used to design better treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098472-06A1
Application #
7730644
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Howcroft, Thomas K
Project Start
2002-12-01
Project End
2011-05-31
Budget Start
2009-06-21
Budget End
2010-05-31
Support Year
6
Fiscal Year
2009
Total Cost
$336,849
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Kulling, Paige M; Olson, Kristine C; Olson, Thomas L et al. (2018) Calcitriol-mediated reduction in IFN-? output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation. J Steroid Biochem Mol Biol 177:140-148
Olson, Kristine C; Kulling Larkin, Paige M; Signorelli, Rossana et al. (2018) Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes. Cytokine 111:551-562
Wang, T Tiffany; Yang, Jun; Zhang, Yong et al. (2018) IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective ?-chain cytokines, decreases leukemic T-cell viability. Leukemia :
Yang, Jun; LeBlanc, Francis R; Dighe, Shubha A et al. (2018) TRAIL mediates and sustains constitutive NF-?B activation in LGL leukemia. Blood 131:2803-2815
Kulling, Paige M; Olson, Kristine C; Hamele, Cait E et al. (2018) Dysregulation of the IFN-?-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia. PLoS One 13:e0193429
Kulling, Paige M; Olson, Kristine C; Olson, Thomas L et al. (2017) Vitamin D in hematological disorders and malignancies. Eur J Haematol 98:187-197
Olson, Kristine C; Kulling, Paige M; Olson, Thomas L et al. (2017) Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia. Cancer Biol Ther 18:290-303
Tan, Su-Fern; Liu, Xin; Fox, Todd E et al. (2016) Acid ceramidase is upregulated in AML and represents a novel therapeutic target. Oncotarget 7:83208-83222
Andersson, Emma I; Tanahashi, Takahiro; Sekiguchi, Nodoka et al. (2016) High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. Blood 128:2465-2468
Sang, Wei; Wang, Ying; Zhang, Cong et al. (2016) MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway. Immunol Lett 172:1-10

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