PMID- 36253429 OWN - NLM STAT- MEDLINE DCOM- 20230201 LR - 20230703 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 37 IP - 1 DP - 2023 Jan TI - Molecular landscape of immune pressure and escape in aplastic anemia. PG - 202-211 LID - 10.1038/s41375-022-01723-w [doi] AB - Idiopathic aplastic anemia (IAA) pathophysiology is dominated by autoreactivity of human leukocyte antigen (HLA)-restricted T-cells against antigens presented by hematopoietic stem and progenitor cells (HSPCs). Expansion of PIGA and HLA class I mutant HSPCs have been linked to immune evasion from T-cell mediated pressures. We hypothesized that in analogy with antitumor immunity, the pathophysiological cascade of immune escape in IAA is initiated by immunoediting pressures and culminates with mechanisms of clonal evolution characterized by hits in immune recognition and response genes. To that end, we studied the genetic and transcriptomic make-up of the antigen presentation complexes in a large cohort of patients with IAA and paroxysmal nocturnal hemoglobinuria (PNH) by using single-cell RNA, high throughput DNA sequencing and single nucleotide polymorphism (SNP)-array platforms. At disease onset, HSPCs displayed activation of selected HLA class I and II-restricted mechanisms, without extensive inhibition of immune checkpoint apparatus. Using a newly implemented bioinformatic framework we found that not only class I but also class II genes were often impaired by acquisition of genetic aberrations. We also demonstrated the presence of novel somatic alterations in immune genes possibly contributing to the evasion from the autoimmune T-cells. In contrast, these hits were absent in myeloid neoplasia. These aberrations were not mutually exclusive with PNH and did not correlate with the accumulation of myeloid-driver hits. Our findings shed light on the mechanisms of immune activation and escape in IAA and define alternative modes of clonal hematopoiesis. CI - (c) 2022. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Pagliuca, Simona AU - Pagliuca S AUID- ORCID: 0000-0003-4688-2478 AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. AD - Department of Hematology, CHRU Nancy, Vandoeuvre-les-Nancy, France. FAU - Gurnari, Carmelo AU - Gurnari C AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. AD - Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy. FAU - Hercus, Colin AU - Hercus C AD - Novocraft Technologies Sdn Bhd, Kuala Lumpur, Malaysia. FAU - Hergalant, Sebastien AU - Hergalant S AUID- ORCID: 0000-0001-8456-7992 AD - Inserm UMR_S1256 Nutrition-Genetics-Environmental Risk Exposure, University of Lorraine, 54500, Vandoeuvre-les-Nancy, France. FAU - Nadarajah, Niroshan AU - Nadarajah N AD - Munich Leukemia Laboratory, MLL, Munich, Germany. FAU - Wahida, Adam AU - Wahida A AD - Munich Leukemia Laboratory, MLL, Munich, Germany. FAU - Terkawi, Laila AU - Terkawi L AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. FAU - Mori, Minako AU - Mori M AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. FAU - Zhou, Weiyin AU - Zhou W AD - Division of Cancer Epidemiology & Genetics, NIH-NCI Clinical Genetics Branch, Rockville, MD, USA. AD - Cancer Genomics Research Laboratory, Frederick National Laboratory, Frederick, MD, USA. FAU - Visconte, Valeria AU - Visconte V AUID- ORCID: 0000-0002-2993-1509 AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. FAU - Spellman, Stephen AU - Spellman S AUID- ORCID: 0000-0002-7271-8252 AD - CIBMTR(R) (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN, USA. FAU - Gadalla, Shahinaz M AU - Gadalla SM AD - Division of Cancer Epidemiology & Genetics, NIH-NCI Clinical Genetics Branch, Rockville, MD, USA. FAU - Zhu, Caiying AU - Zhu C AD - State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, No. 288 Nanjing Rd, Tianjin, China. FAU - Zhu, Ping AU - Zhu P AUID- ORCID: 0000-0002-4521-7524 AD - State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, No. 288 Nanjing Rd, Tianjin, China. FAU - Haferlach, Torsten AU - Haferlach T AUID- ORCID: 0000-0003-0196-2837 AD - Munich Leukemia Laboratory, MLL, Munich, Germany. FAU - Maciejewski, Jaroslaw P AU - Maciejewski JP AUID- ORCID: 0000-0002-6837-4346 AD - Translational Hematology and Oncology Research Program, Cleveland Clinic, Cleveland, OH, USA. maciejj@ccf.org. LA - eng GR - R01 HL128425/HL/NHLBI NIH HHS/United States GR - R01 HL118281/HL/NHLBI NIH HHS/United States GR - U24 CA076518/CA/NCI NIH HHS/United States GR - R35 HL135795/HL/NHLBI NIH HHS/United States GR - R01 HL123904/HL/NHLBI NIH HHS/United States GR - R01 HL132071/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. DEP - 20221017 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Histocompatibility Antigens Class I) RN - Aplastic anemia, idiopathic SB - IM MH - Humans MH - *Anemia, Aplastic/genetics/pathology MH - Hematopoietic Stem Cells/pathology MH - *Hemoglobinuria, Paroxysmal/genetics/pathology MH - Histocompatibility Antigens Class I/genetics MH - Polymorphism, Single Nucleotide PMC - PMC10089624 MID - NIHMS1852581 COIS- Conflict-of-interest disclosure: This research was conducted in absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Collaboration between Cleveland Clinic and Novocraft was based on a no-profit academic partnership. EDAT- 2022/10/18 06:00 MHDA- 2023/02/01 06:00 PMCR- 2023/07/01 CRDT- 2022/10/17 23:21 PHST- 2022/07/09 00:00 [received] PHST- 2022/10/04 00:00 [accepted] PHST- 2022/09/25 00:00 [revised] PHST- 2022/10/18 06:00 [pubmed] PHST- 2023/02/01 06:00 [medline] PHST- 2022/10/17 23:21 [entrez] PHST- 2023/07/01 00:00 [pmc-release] AID - 10.1038/s41375-022-01723-w [pii] AID - 10.1038/s41375-022-01723-w [doi] PST - ppublish SO - Leukemia. 2023 Jan;37(1):202-211. doi: 10.1038/s41375-022-01723-w. Epub 2022 Oct 17.