Oncotarget

Research Papers:

Survival in acute myeloid leukemia is associated with NKp44 splice variants

Avishai Shemesh, Michael Brusilovsky, Uzi Hadad, Omri Teltsh, Avishay Edri, Eitan Rubin, Kerry S. Campbell, Benyamin Rosental and Angel Porgador _

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Oncotarget. 2016; 7:32933-32945. https://doi.org/10.18632/oncotarget.8782

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Abstract

Avishai Shemesh1,2,*, Michael Brusilovsky1,*, Uzi Hadad1, Omri Teltsh1, Avishay Edri1, Eitan Rubin1, Kerry S. Campbell3, Benyamin Rosental4, Angel Porgador1,2

1The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

2National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

3Immune Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA

4Institute 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 NKp44ITIM+ (NKp44-1) and NKp44ITIM- (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.


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