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

Blood. 2008 Dec 1;112(12):4694-8. doi: 10.1182/blood-2008-02-136382. Epub 2008 Sep 12.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Cells, Cultured
  • Enzyme Inhibitors / therapeutic use
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Female
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / etiology
  • K562 Cells
  • Leukemia, Large Granular Lymphocytic / complications
  • Leukemia, Large Granular Lymphocytic / drug therapy*
  • Leukemia, Large Granular Lymphocytic / genetics
  • Middle Aged
  • Quinolones / therapeutic use
  • Receptors, Natural Killer Cell / genetics*
  • Signal Transduction / genetics
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Quinolones
  • Receptors, Natural Killer Cell
  • Farnesyltranstransferase
  • tipifarnib