Related Experiment Video
Updated: May 5, 2026
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating
H Yang1, C Bueso-Ramos2, C DiNardo1
1Department of Leukemia, 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.
Insights
Immune checkpoint blockade, targeting programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1), shows promise for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Upregulation of these pathways is linked to MDS pathogenesis and resistance to epigenetic therapy.
Area of Science:
- Immunology
- Oncology
- Hematology
Background:
- Immune checkpoint blockade represents a novel anticancer therapeutic strategy.
- Programmed death ligand 1 (PD-L1), PD-L2, programmed death 1 (PD-1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) are key immune checkpoints.
- Myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) are hematologic malignancies with complex immune interactions.
Purpose of the Study:
- To investigate the expression of PD-L1, PD-L2, PD-1, and CTLA4 mRNA in hematopoietic stem and progenitor cells (CD34+) and peripheral blood mononuclear cells (PBMNCs) from patients with MDS, CMML, and AML.
- To evaluate the correlation between immune checkpoint gene expression and response to epigenetic therapy.
- To explore the role of PD-1 signaling in MDS pathogenesis and resistance to hypomethylating agents.
Main Methods:
- Quantitative mRNA expression analysis of PD-L1, PD-L2, PD-1, and CTLA4 in CD34+ cells and PBMNCs from 124 MDS, CMML, and AML patients.
- Immunohistochemical analysis to determine PD-L1 and PD-1 protein expression.
- Analysis of immune checkpoint gene expression in patients undergoing epigenetic therapy, including decitabine treatment of leukemia cell lines and patient samples.
Main Results:
- Aberrant upregulation (⩾2-fold) of PD-L1, PD-L2, PD-1, and CTLA4 mRNA was observed in 34%, 14%, 15%, and 8% of patients, respectively.
- PD-L1 expression was significantly higher in PBMNCs from MDS and CMML patients compared to AML patients.
- PD-L1 protein was detected in MDS CD34+ cells, while PD-1 was found in the stroma/non-blast compartment. Immune checkpoint gene expression increased with epigenetic therapy, with higher increments in therapy-resistant patients. Decitabine treatment induced dose-dependent upregulation of these genes and partial demethylation of PD-1.
Conclusions:
- PD-1 signaling pathway involvement in MDS pathogenesis and resistance mechanisms to hypomethylating agents is suggested.
- Upregulation of PD-1, PD-L1, PD-L2, and CTLA4 is associated with epigenetic therapy resistance in MDS and AML.
- Blockade of the PD-1 pathway presents a potential therapeutic strategy for MDS and AML.
