KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target - Archive ouverte HAL Access content directly
Journal Articles Blood Year : 2022

KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target

Ludovic Lhermitte
  • Function : Author
Julie Bruneau
Hélène Sicard
  • Function : Author
Cécile Bonnafous
  • Function : Author
Aurore Touzart
  • Function : Author
Estelle Bourbon
  • Function : Author
Nicolas Ortonne
Laurent Genestier
  • Function : Author
Philippe Gaulard
  • Function : Author
Patricia Palmic
  • Function : Author
Felipe Suarez
Laurent Frenzel
Louise Naveau
  • Function : Author
Ali Bazarbachi
  • Function : Author
Mickaël Dussiot
  • Function : Author
Véronique Avettand-Fenoel
Chantal Brouzes
  • Function : Author
Yves Lepelletier
  • Function : Author
Vahid Asnafi
  • Function : Author
Ambroise Marçais
  • Function : Author
Olivier Hermine
  • Function : Author


Abstract 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 as #NCT04984837).
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Dates and versions

hal-03828619 , version 1 (25-10-2022)



Morgane Cheminant, Ludovic Lhermitte, Julie Bruneau, Hélène Sicard, Cécile Bonnafous, et al.. KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target. Blood, 2022, 140 (13), pp.1522-1532. ⟨10.1182/blood.2022016765⟩. ⟨hal-03828619⟩


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