title: Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling.
abstract: 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.
authors.affiliation: Department of Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute Immunology Program, James A Haley Veterans Administration Hospital, University of South Florida, Tampa, FL 33612, USA. Pearlie.Burnette@moffitt.org
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Xianhong
authors.initials: X
authors.lastname: Chen
authors.forename: Fanqi
authors.initials: F
authors.lastname: Bai
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhou
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: JianXiang
authors.initials: J
authors.lastname: Zou
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Painter
authors.forename: Todd D
authors.initials: TD
authors.lastname: Edwards
authors.forename: Lynn
authors.initials: L
authors.lastname: Moscinski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Yoder
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology; D020014:K562 Cells; D054066:Leukemia, Large Granular Lymphocytic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D015363:Quinolones / Q000627:therapeutic use; D055607:Receptors, Natural Killer Cell / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D055607:Receptors, Natural Killer Cell; D051231:Farnesyltranstransferase; C402769:tipifarnib
references.citation: Blood. 1994 Sep 1;84(5):1361-92
references.pmid: 8068936
references.citation: Oncogene. 2004 Dec 9;23(57):9220-9
references.pmid: 15516985
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12433-8
references.pmid: 8901599
references.citation: Ann Intern Med. 1985 Feb;102(2):169-75
references.pmid: 3966754
references.citation: N Engl J Med. 1997 Jan 9;336(2):111-7
references.pmid: 8988890
references.citation: Ann Intern Med. 1987 Aug;107(2):216-23
references.pmid: 3605900
references.citation: J Immunol. 2000 Oct 1;165(7):3811-9
references.pmid: 11034387
references.citation: Br J Haematol. 2007 Jan;136(2):237-48
references.pmid: 17156396
references.citation: Chest. 1997 Aug;112(2):551-3
references.pmid: 9266900
references.citation: Immunol Rev. 1997 Feb;155:145-54
references.pmid: 9059890
references.citation: Blood. 2004 May 1;103(9):3431-9
references.pmid: 14726391
references.citation: Exp Hematol. 2005 Nov;33(11):1357-62
references.pmid: 16263420
references.citation: J Exp Med. 1999 Dec 6;190(11):1627-36
references.pmid: 10587353
references.citation: J Biol Chem. 1998 Dec 18;273(51):34115-9
references.pmid: 9852069
references.citation: Br J Haematol. 2000 Mar;108(4):717-23
references.pmid: 10792274
references.citation: J Exp Med. 2001 Aug 20;194(4):455-69
references.pmid: 11514602
references.citation: Immunity. 1998 Jun;8(6):693-701
references.pmid: 9655483
references.citation: Blood. 1993 Jul 1;82(1):1-14
references.pmid: 8324214
references.citation: Curr Opin Immunol. 2005 Feb;17(1):29-35
references.pmid: 15653307
references.citation: Immunol Today. 2000 Dec;21(12):611-4
references.pmid: 11114420
references.citation: Science. 1999 Jul 30;285(5428):727-9
references.pmid: 10426993
references.citation: Annu Rev Immunol. 2001;19:197-223
references.pmid: 11244035
references.citation: J Clin Invest. 2002 Jan;109(2):161-8
references.pmid: 11805126
references.citation: J Exp Med. 2000 Oct 2;192(7):1059-68
references.pmid: 11015446
references.citation: Blood. 2003 Sep 1;102(5):1797-805
references.pmid: 12750175