Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:32881.

Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition

Aroa Baragaño Raneros, Alfredo Minguela, Ramon M. Rodriguez, Enrique Colado, Teresa Bernal, Eduardo Anguita, Adela Vasco Mogorron, Alberto Chaparro Gil, Jose Ramon Vidal-Castiñeira, Leonardo Márquez-Kisinousky, Paula Díaz Bulnes, Amelia Martinez Marin, Maria Carmen García Garay, Beatriz Suarez-Alvarez and Carlos Lopez-Larrea _

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Oncotarget. 2017; 8:31959-31976. https://doi.org/10.18632/oncotarget.16657

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Aroa Baragaño Raneros1, Alfredo Minguela2, Ramon M. Rodriguez1, Enrique Colado3, Teresa Bernal3, Eduardo Anguita4, Adela Vasco Mogorron2, Alberto Chaparro Gil4, Jose Ramon Vidal-Castiñeira1, Leonardo Márquez-Kisinousky1, Paula Díaz Bulnes1, Amelia Martinez Marin5, Maria Carmen García Garay6, Beatriz Suarez-Alvarez1,*, Carlos Lopez-Larrea1,*

1Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain

2Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

3Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain

4Hematology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Department of Medicine, Universidad Complutense de Madrid (UCM), Madrid, Spain

5Hematology Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

6Hematology Service, Hospital General Universitario Santa Lucía, Cartagena, Murcia, Spain

*These authors have contributed equally to this work

Correspondence to:

Carlos Lopez-Larrea, email: [email protected]

Beatriz Suarez-Alvarez, email: [email protected]

Keywords: acute myeloid leukemia (AML), DNA methylation, NKG2DL, NKG2D, TIMP3

Received: September 16, 2016     Accepted: March 16, 2017     Published: March 29, 2017


Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.

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