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Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis

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Abstract

Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients.

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Abbreviations

CR:

Complete remission

NK:

Natural killer

AML:

Acute myeloid leukemia

TF:

Transcription factor

NCR:

Natural cytotoxicity receptor

EBV:

Epstein barr virus

PBMC:

Peripheral blood mononuclear cells

p:

p values

FC:

Fold change

TFBS:

Transcription factor binding sites

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Acknowledgments

We would like to thank INSERM, AP-HM and Aix-Marseille University for grants. We would like to thanks Martin VILLALBA who gave us graciously EBV cell line. We are grateful to the patients who gave their informed consent to the use of their samples for research. We are grateful to the IBiSA Transcriptomics and Genomics Marseille-Luminy (TGML) platform were supported by the France Génomique National infrastructure. We thank Laurence Borge for assistance and the use of the cell culture platform facilities (CRCM U1068, Marseille) Plateforme de Culture Cellulaire de Marseille-Luminy, bâtiment TPR2, 163 Avenue de Luminy, 13009 Marseille. We thank also Geneviève Victorero for technical supports. This work was supported by grants from AP-HM, Assistance Publique—Hôpitaux de Marseille, (AORC APHM Junior), and Aix-Marseille Université, TGML platform supported by the France Génomique.

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Author notes

  1. R. Costello

    Present address: Service d’Hématologie et de Thérapie Cellulaire Assistance Publique des Hôpitaux de Marseille, Centre Hospitalier Universitaire La Conception, 147 boulevard Baille, Marseille, 13005, France

Authors and Affiliations

  1. INSERM, UMR1090, Aix-Marseille Université, TAGC Campus de Luminy, Marseille, 13288, France

    G. Venton, Y. Labiad, J. Colle, A. Fino, S. Afridi, M. Torres, S. Monteuil, B. Loriod, N. Fernandez-Nunez, P. Rihet, A. Bergon, C. Nguyen, C. Baier & R. Costello

  2. Service d’Hématologie et de Thérapie Cellulaire Assistance Publique des Hôpitaux de Marseille, Centre Hospitalier Universitaire La Conception, 147 boulevard Baille, Marseille, 13005, France

    G. Venton, J. Colle & L. Farnault

  3. Laboratoire d’Hématologie, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalier Universitaire La Timone, Marseille, France

    P. Suchon

  4. UMR 1062 NORT, INSERM, Marseille, France

    P. Suchon

  5. Faculté de Médecine, UMR-911 INSERM Center for Research in Onco-biology and Onco-pharmacology, Marseille, France

    J. C. Mattei

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Corresponding author

Correspondence to R. Costello.

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All authors declare no financial conflict of interest.

Additional information

G. Venton and Y. Labiad have contributed equally to this work.

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Venton, G., Labiad, Y., Colle, J. et al. Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis. Immunol Res 64, 1225–1236 (2016). https://doi.org/10.1007/s12026-016-8848-0

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