Molecular landscape of immune pressure and escape in aplastic anemia.
Fiche publication
Date publication
janvier 2023
Journal
Leukemia
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PAGLIUCA Simona
Tous les auteurs :
Pagliuca S, Gurnari C, Hercus C, Hergalant S, Nadarajah N, Wahida A, Terkawi L, Mori M, Zhou W, Visconte V, Spellman S, Gadalla SM, Zhu C, Zhu P, Haferlach T, Maciejewski JP
Lien Pubmed
Résumé
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.
Mots clés
Humans, Anemia, Aplastic, genetics, Hematopoietic Stem Cells, pathology, Hemoglobinuria, Paroxysmal, genetics, Histocompatibility Antigens Class I, genetics, Polymorphism, Single Nucleotide
Référence
Leukemia. 2023 01;37(1):202-211