PMID- 31898344 OWN - NLM STAT- MEDLINE DCOM- 20210709 LR - 20210709 IS - 1097-4644 (Electronic) IS - 0730-2312 (Linking) VI - 121 IP - 5-6 DP - 2020 Jun TI - PTPN21-CDS(long) isoform inhibits the response of acute lymphoblastic leukemia cells to NK-mediated lysis via the KIR/HLA-I axis. PG - 3298-3312 LID - 10.1002/jcb.29601 [doi] AB - Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a member of the non-receptor tyrosine phosphatase family. We have found that PTPN21 is mutated in relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation. PTPN21 consists of three types of isoforms according to the length of the protein encoded. However, the roles of different isoforms in leukemic cells have not been elucidated. In the study, PTPN21 isoform constitution in five ALL cell lines were identified by transcriptome polymerase chain reaction combined with Sanger sequencing, and the relationship between PTPN21 isoforms and sensitivity to natural killer (NK) cells mediated killing in ALL cell lines were further assessed by knock-out of different isoforms of PTPN21 using CRISPR-Cas9 technique. Subsequently, we explored the functional mechanisms through RNA sequencing and confirmatory testing. The results showed that there was no significant change when all PTPN21 isoforms were knocked out in ALL cells, but the sensitivity of NALM6 cells with PTPN21-CDS(long) knock-out (NALM6-PTPN21(lk) ) to NK-mediated killing was significantly increased. Whole transcriptome sequencing and further validation testing showed that human leukocyte antigen class I (HLA-I) molecules were significantly decreased, accompanied by a significantly downregulated expression of antigen presenting-related chaperones in NALM6-PTPN21(lk) cells. Our results uncovered a previously unknown mechanism that PTPN21-CDS(long) and CDS(short) isoforms may play opposite roles in NK-mediated killing in ALL cells, and showed that the endogenous PTPN21-CDS(long) isoform inhibited ALL cells to NK cell-mediated lysis by regulating the KIR-HLA-I axis. CI - (c) 2020 Wiley Periodicals, Inc. FAU - Wang, Huafang AU - Wang H AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. AD - Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China. FAU - Zhu, Ni AU - Zhu N AD - Department of Hematology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China. FAU - Ye, Xiaohang AU - Ye X AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Wang, Limengmeng AU - Wang L AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. AD - Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China. FAU - Wang, Binsheng AU - Wang B AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. AD - Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China. FAU - Shan, Wei AU - Shan W AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. AD - Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China. FAU - Lai, Xiaoyu AU - Lai X AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Tan, Yamin AU - Tan Y AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Fu, Shan AU - Fu S AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. FAU - Xiao, Haowen AU - Xiao H AD - Department of Hematology, The Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. FAU - Huang, He AU - Huang H AUID- ORCID: 0000-0002-2723-1621 AD - Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. AD - Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. AD - Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200102 PL - United States TA - J Cell Biochem JT - Journal of cellular biochemistry JID - 8205768 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Molecular Chaperones) RN - 0 (Protein Isoforms) RN - EC 3.1.3.2 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTPN21 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor) SB - IM MH - CRISPR-Cas Systems MH - Cell Death MH - Cell Line, Tumor MH - Cytotoxicity, Immunologic/immunology MH - Gene Editing MH - *Gene Expression Regulation, Leukemic MH - Histocompatibility Antigens Class I/immunology MH - Humans MH - Killer Cells, Natural/immunology/metabolism MH - Molecular Chaperones/metabolism MH - Phosphoric Monoester Hydrolases/metabolism MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*metabolism MH - Protein Isoforms MH - Protein Tyrosine Phosphatases, Non-Receptor/*chemistry/*metabolism MH - RNA-Seq OTO - NOTNLM OT - NK killing OT - acute lymphoblastic leukemia OT - human leukocyte antigens class I molecules OT - isoform OT - protein tyrosine phosphatase non-receptor type 21 EDAT- 2020/01/04 06:00 MHDA- 2021/07/10 06:00 CRDT- 2020/01/04 06:00 PHST- 2019/07/24 00:00 [received] PHST- 2019/12/11 00:00 [accepted] PHST- 2020/01/04 06:00 [pubmed] PHST- 2021/07/10 06:00 [medline] PHST- 2020/01/04 06:00 [entrez] AID - 10.1002/jcb.29601 [doi] PST - ppublish SO - J Cell Biochem. 2020 Jun;121(5-6):3298-3312. doi: 10.1002/jcb.29601. Epub 2020 Jan 2.