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Leukemia. 2014 Jun;28(6):1280-8. doi: 10.1038/leu.2013.355. Epub 2013 Nov 25.

Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents.

Author information

1
Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA.
2
Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX, USA.
3
1] Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA [2] Department of Molecular Carcinogenesis, University of Texas MD Cancer Center, Houston, TX, USA.
4
1] Department of Leukemia, University of Texas MD Cancer Center, Houston, TX, USA [2] Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
5
Department of Stem Cell Transplantation, University of Texas MD Cancer Center, Houston, TX, USA.

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.

PMID:
24270737
PMCID:
PMC4032802
DOI:
10.1038/leu.2013.355
[Indexed for MEDLINE]
Free PMC Article

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