Fiche publication
Date publication
septembre 2022
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MARCAIS Ambroise
Tous les auteurs :
Cheminant M, Lhermitte L, Bruneau J, Sicard H, Bonnafous C, Touzart A, Bourbon E, Ortonne N, Genestier L, Gaulard P, Palmic P, Suarez F, Frenzel L, Naveau L, Bazarbachi A, Dussiot M, Waast L, Avettand-Fenoel V, Brouzes C, Pique C, Lepelletier Y, Asnafi V, Marçais A, Hermine O
Lien Pubmed
Résumé
Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2+ primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837).
Mots clés
Adult, Gene Products, tax, genetics, HTLV-I Infections, complications, Human T-lymphotropic virus 1, genetics, Humans, Leukemia-Lymphoma, Adult T-Cell, pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, RNA, RNA, Messenger, Receptors, KIR3DL2, genetics
Référence
Blood. 2022 09 29;140(13):1522-1532
