The broad long term of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with autoimmune disease. Our central hypothesis is that LGL leukemia results from dysregulated apoptosis. The goal of this proposal is to understand the mechanisms of treatment response in this model by pursuing correlative laboratory studies associated with an ECOG trial. Patients with neutropenia or anemia will initially receive oral methotrexate. Patients failing to respond to methotrexate will then receive oral cyclophosphamide. Samples from patients receiving cyclosporine on a CALGB study will also be evaluated.
Each specific aim will test a postulated mechanism of treatment efficacy:
Specific Aim 1 : To determine if treatment induces apoptosis in leukemic LGL;
Specific Aim 2 : To determine if treatment results in decreased secretion of Fas ligand;
Specific Aim 3 : To determine if treatment response is related to constitutive STAT signaling and regulation of STAT-responsive genes. Correlative studies in Specific Aim 1 include development of a predictive in vitro apoptotic assay and measurement of decoy Fas receptors on treatment. Mechanistic studies will investigate the mitochondrial-dependent apoptotic pathway induced by MTX. Correlative studies in Specific Aim 2 will measure levels of Fas ligand on treatment. Mechanistic studies will examine regulation of Fas ligand gene transcription. Correlative studies in Specific Aim 3 will measure levels of STAT activation and Mcl-1 protein expression on treatment. Treatment effects on expression of STAT-regulated genes will be examined using microarray analyses. Results of these studies should identify important molecular targets for drug development in hematologic malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA090633-01
Application #
6322267
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
2001-04-03
Project End
2006-03-31
Budget Start
2001-04-03
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$300,875
Indirect Cost
Name
University of South Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Shah, Mithun Vinod; Zhang, Ranran; Irby, Rosalyn et al. (2008) Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes. Blood 112:770-81
Kothapalli, Ravi; Nyland, Susan B; Kusmartseva, Irina et al. (2005) Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. Int J Oncol 26:529-35
Epling-Burnette, Pearlie K; Bai, Fanqi; Wei, Sheng et al. (2004) ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene 23:9220-9
Epling-Burnette, Pearlie Kay; Painter, Jeffrey S; Chaurasia, Pratima et al. (2004) Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes. Blood 103:3431-9
Kothapalli, Ravi; Yoder, Sean J; Kusmartseva, Irina et al. (2003) Characterization of a variant of PAC-1 in large granular lymphocyte leukemia. Protein Expr Purif 32:52-60
Epling-Burnette, P K; Loughran Jr, Thomas P (2003) Survival signals in leukemic large granular lymphocytes. Semin Hematol 40:213-20
Kothapalli, Ravi; Bailey, Ratna D; Kusmartseva, Irina et al. (2003) Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors in LGL leukemia. Int J Oncol 22:33-9
Kothapalli, Ravi; Danyluck, Gregory M; Bailey, Ratna D et al. (2003) Problems associated with product enhancement reverse transcriptase assay using bacteriophage MS2 RNA as a template. J Virol Methods 109:203-7
Kothapalli, Ravi; Kusmartseva, Irina; Loughran, Thomas P (2002) Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its differential expression in LGL leukemia. Biochim Biophys Acta 1579:117-23

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