Abstract
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.
Highlights
Acute myeloid leukemia (AML) is characterized by the accumulation of myeloid precursors in bone marrow and peripheral blood [1]
Results demonstrated that AZA- and DAC-treated AML cells reduce the release of soluble NKG2DL (sNKG2DL), preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2D receptor with its ligands (NKG2DL) engagement
We show that (i) AZA and DAC limit the release of all NKG2DL in the supernatants of AML cell lines; (ii) decreased levels of sNKG2DL prevent the downregulation of the NKG2D receptor and favor the recognition and lysis of AML cells by NKL cells; (iii) ADAM17 is the sheddase involved in the release of sNKG2DL in AML cell lines; (iv) demethylation of tissue inhibitor of metalloproteinases-3 (TIMP3) gene may be responsible for the lower level of shedding of MICA, MICB and ULBP2 in AML cells; and (v) high TIMP3 DNA methylation levels in AML patients are associated with an adverse cytogenetic prognosis for the disease
Summary
Acute myeloid leukemia (AML) is characterized by the accumulation of myeloid precursors in bone marrow and peripheral blood [1]. Since 2008, and extended in 2016, the World Health Organization (WHO) has characterized AML patients with respect to specific genetic abnormalities [2] Both classifications reveal the considerable clinical and biological heterogeneity of this disease, but the therapeutic options remains very limited. Azacytidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) are cytidine nucleoside analogs whose main advantage over conventional care regimens is less toxicity of the drug, better tolerability and better overall survival of AML patients [4,5,6]. These hypomethylating drugs affect cell viability, cell cycle, and changes in gene expression profiles [7]. Knowing the molecular patterns that are modulated by these agents could be essential to improving their effectiveness and for identifying new biomarkers that predict the response to these drugs
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