TY - JOUR
T1 - Survival in acute myeloid leukemia is associated with NKp44 splice variants
AU - Shemesh, Avishai
AU - Brusilovsky, Michael
AU - Hadad, Uzi
AU - Teltsh, Omri
AU - Edri, Avishay
AU - Rubin, Eitan
AU - Campbell, Kerry S.
AU - Rosental, Benyamin
AU - Porgador, Angel
N1 - Funding Information:
This work was supported by US/Israel Binational Science Foundation grant 2011123 (A.P. and K.S.C.), NIH Cancer Center Support Grant CA06927 (K.S.C.), Israel Science Foundation grant 304/12 (A.P.), the Israeli Ministry of Science and Technology/German Cancer Research Center program Grant CA142 (A.P.) and the upstart-FOHS grant (E.R. and A.P.).
PY - 2016/5/31
Y1 - 2016/5/31
N2 - 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.
AB - 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.
KW - AML
KW - Isoforms
KW - NKp44
KW - Natural killer cells
KW - Splice variants
UR - http://www.scopus.com/inward/record.url?scp=84973531037&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8782
DO - 10.18632/oncotarget.8782
M3 - Article
AN - SCOPUS:84973531037
SN - 1949-2553
VL - 7
SP - 32933
EP - 32945
JO - Oncotarget
JF - Oncotarget
IS - 22
ER -