Abstract
Blockade of immune checkpoints is emerging as a new form of anticancer therapy. We studied the expression of programmed death ligand 1 (PD-L1), PD-L2, programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) mRNA in CD34+ cells from myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) patients (N=124). Aberrant upregulation (⩾2-fold) was observed in 34, 14, 15 and 8% of the patients. Increased expression of these four genes was also observed in peripheral blood mononuclear cells (PBMNCs) (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (P=0.018) and CMML (P=0.0128) compared with AML. By immunohistochemical analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared with patients who achieved response. Treatment of leukemia cells with decitabine resulted in a dose-dependent upregulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests that PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to hypomethylating agents. Blockade of this pathway can be a potential therapy in MDS and AML.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antimetabolites, Antineoplastic / pharmacology
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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B7-H1 Antigen / genetics*
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B7-H1 Antigen / metabolism
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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CTLA-4 Antigen / genetics*
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CTLA-4 Antigen / metabolism
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Cohort Studies
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DNA Methylation
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Decitabine
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Female
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Flow Cytometry
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Humans
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Immunoenzyme Techniques
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Leukemia, Myeloid, Acute / drug therapy
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / mortality
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Leukemia, Myelomonocytic, Chronic / drug therapy
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Leukemia, Myelomonocytic, Chronic / genetics*
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Leukemia, Myelomonocytic, Chronic / mortality
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Male
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Middle Aged
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Myelodysplastic Syndromes / drug therapy
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Myelodysplastic Syndromes / genetics*
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Myelodysplastic Syndromes / mortality
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Prognosis
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Programmed Cell Death 1 Ligand 2 Protein / genetics*
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Programmed Cell Death 1 Ligand 2 Protein / metabolism
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Programmed Cell Death 1 Receptor / genetics*
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Programmed Cell Death 1 Receptor / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Rate
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Tumor Cells, Cultured
Substances
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Antimetabolites, Antineoplastic
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B7-H1 Antigen
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Biomarkers, Tumor
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CD274 protein, human
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CTLA-4 Antigen
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CTLA4 protein, human
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PDCD1 protein, human
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PDCD1LG2 protein, human
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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RNA, Messenger
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Decitabine
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Azacitidine