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High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

  • Chretien, Anne-Sophie1, 2
  • Devillier, Raynier1, 2, 3
  • Granjeaud, Samuel3
  • Cordier, Charlotte1, 2, 2
  • Demerle, Clemence1, 2
  • Salem, Nassim1, 2
  • Wlosik, Julia1, 2
  • Orlanducci, Florence1, 2
  • Gorvel, Laurent1, 2
  • Fattori, Stephane1, 2
  • Hospital, Marie-Anne3
  • Pakradouni, Jihane2
  • Gregori, Emilie4
  • Paul, Magali1, 5
  • Rochigneux, Philippe1, 2, 2
  • Pagliardini, Thomas1, 2, 3
  • Morey, Mathieu5
  • Fauriat, Cyril1, 2
  • Dulphy, Nicolas6, 7
  • Toubert, Antoine6, 7
  • And 6 more
  • 1 Aix-Marseille University, France , (France)
  • 2 Institut Paoli-Calmettes, France , (France)
  • 3 Aix-Marseille University UM105, France , (France)
  • 4 Aix Marseille University UMS3367, France , (France)
  • 5 R&D department, France , (France)
  • 6 Université de Paris, France , (France)
  • 7 Hôpital Saint-Louis, France , (France)
Published Article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Publication Date
May 28, 2021
DOI: 10.1073/pnas.2020459118
PMID: 34050021
PMCID: PMC8179170
PubMed Central
  • Biological Sciences
  • Medical Sciences


Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56−CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML ( n = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects ( n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56−CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56−CD16+ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56−CD16+ NK cells. Overall, our data suggest that the accumulation of CD56−CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.

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