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, Angel Porgador

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

NKp44 is a receptor encoded by the NCR2 gene, which is expressed by cytokineactivated 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 PCNAmediated 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.

Original languageEnglish
Pages (from-to)32933-32945
Number of pages13
JournalOncotarget
Volume7
Issue number22
DOIs
StatePublished - 31 May 2016

Keywords

  • AML
  • Isoforms
  • NKp44
  • Natural killer cells
  • Splice variants

ASJC Scopus subject areas

  • Oncology

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