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 Blood, 1 December 2008, Vol. 112, No. 12, pp. 4694-4698.
Prepublished online as a Blood First Edition Paper on September 12, 2008; DOI 10.1182/blood-2008-02-136382.

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NEOPLASIA

Brief Report

Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling

P. K. Epling-Burnette1,2,*, Lubomir Sokol3,*, Xianhong Chen1, Fanqi Bai1, Junmin Zhou1, Michelle A. Blaskovich1, JianXiang Zou1, Jeffrey S. Painter1, Todd D. Edwards4, Lynn Moscinski5, Jeffrey A. Yoder6, Julie Y. Djeu1, Said Sebti1, Thomas P. Loughran, Jr7,{dagger}, and Sheng Wei1,{dagger}

1 H. Lee Moffitt Cancer Center and Research Institute Immunology Program, Department of Interdisciplinary Oncology, 2 James A. Haley Veterans Administration Hospital, and 3 H. Lee Moffitt Cancer Center and Research Institute, Malignant Hematology Division, Department of Interdisciplinary Oncology, University of South Florida, Tampa; 4 The Stern Cardiovascular Center Wolf River, Germantown, TN; 5 H. Lee Moffitt Cancer Center and Research Institute, Pathology Division, Department of Interdisciplinary Oncology, University of South Florida, Tampa; 6 Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh; and 7 Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.


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