Survival in acute myeloid leukemia is associated with NKp44 splice variants. Academic Article uri icon

abstract

  • // Avishai Shemesh 1, 2, * , Michael Brusilovsky 1, * , Uzi Hadad 1 , Omri Teltsh 1 , Avishay Edri 1 , Eitan Rubin 1 , Kerry S. Campbell 3 , Benyamin Rosental 4 , Angel Porgador 1, 2 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel 2 National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel 3 Immune Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA 4 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine and the Hopkins Marine Station, Stanford, CA, USA * These authors have contributed equally to this work Correspondence to: Angel Porgador, email: angel@bgu.ac.il Keywords: AML, NKp44, splice variants, isoforms, natural killer cells Received: February 15, 2016     Accepted: March 27, 2016     Published: April 18, 2016 ABSTRACT NKp44 is a receptor encoded by the NCR2 gene, which is expressed by cytokine-activated natural killer (NK) cells that are involved in anti-AML immunity. NKp44 has three splice variants corresponding to NKp44 ITIM+ (NKp44-1) and NKp44 ITIM- (NKp44-2, and NKp44-3) isoforms. RNAseq data of AML patients revealed similar survival of NKp46 + NKp44 + and NKp46 + NKp44 - patients. However, if grouped according to the NKp44 splice variant profile, NKp44-1 expression was significantly associated with poor survival of AML patients. Moreover, activation of PBMC from healthy controls showed co-dominant expression of NKp44-1 and NKp44-3, while primary NK clones show more diverse NKp44 splice variant profiles. Cultured primary NK cells resulted in NKp44-1 dominance and impaired function associated with PCNA over-expression by target cells. This impaired functional phenotype could be rescued by blocking of NKp44 receptor. Human NK cell lines revealed co-dominant expression of NKp44-1 and NKp44-3 and showed a functional phenotype that was not inhibited by PCNA over-expression. Furthermore, transfection-based overexpression of NKp44-1, but not NKp44-2/NKp44-3, reversed the endogenous resistance of NK-92 cells to PCNA-mediated inhibition, and resulted in poor formation of stable lytic immune synapses. This research contributes to the understanding of AML prognosis by shedding new light on the functional implications of differential splicing of NKp44.

publication date

  • May 1, 2016