Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling.
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.
Epling-Burnette
P K
PK
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
Sokol
Lubomir
L
Chen
Xianhong
X
Bai
Fanqi
F
Zhou
Junmin
J
Blaskovich
Michelle A
MA
Zou
JianXiang
J
Painter
Jeffrey S
JS
Edwards
Todd D
TD
Moscinski
Lynn
L
Yoder
Jeffrey A
JA
Djeu
Julie Y
JY
Sebti
Said
S
Loughran
Thomas P
TP
Wei
Sheng
S
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D055607:Receptors, Natural Killer Cell; D051231:Farnesyltranstransferase; C402769:tipifarnib
Blood. 1994 Sep 1;84(5):1361-92
8068936
Oncogene. 2004 Dec 9;23(57):9220-9
15516985
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12433-8
8901599
Ann Intern Med. 1985 Feb;102(2):169-75
3966754
N Engl J Med. 1997 Jan 9;336(2):111-7
8988890
Ann Intern Med. 1987 Aug;107(2):216-23
3605900
J Immunol. 2000 Oct 1;165(7):3811-9
11034387
Br J Haematol. 2007 Jan;136(2):237-48
17156396
Chest. 1997 Aug;112(2):551-3
9266900
Immunol Rev. 1997 Feb;155:145-54
9059890
Blood. 2004 May 1;103(9):3431-9
14726391
Exp Hematol. 2005 Nov;33(11):1357-62
16263420
J Exp Med. 1999 Dec 6;190(11):1627-36
10587353
J Biol Chem. 1998 Dec 18;273(51):34115-9
9852069
Br J Haematol. 2000 Mar;108(4):717-23
10792274
J Exp Med. 2001 Aug 20;194(4):455-69
11514602
Immunity. 1998 Jun;8(6):693-701
9655483
Blood. 1993 Jul 1;82(1):1-14
8324214
Curr Opin Immunol. 2005 Feb;17(1):29-35
15653307
Immunol Today. 2000 Dec;21(12):611-4
11114420
Science. 1999 Jul 30;285(5428):727-9
10426993
Annu Rev Immunol. 2001;19:197-223
11244035
J Clin Invest. 2002 Jan;109(2):161-8
11805126
J Exp Med. 2000 Oct 2;192(7):1059-68
11015446
Blood. 2003 Sep 1;102(5):1797-805
12750175