Phagocytosis checkpoints on hematopoietic stem cells in patients with myelodysplastic syndromes
Xifeng Dong1, Yu Han2, Yumei Liu1
1Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, China.
Background:
The myelodysplastic syndrome (MDS) is a high-risk hemocytopenia easily converted to acute myeloid leukemia. CD47 plays an important role in regulating phagocytosis, and its role in the pathogenesis of MDS is unclear.
Methods:
CD47 and PI3K/AKT/mTOR on CD34+ CD38- cells were detected by flow cytometry. NF-κB, PI3K, AKT, PTEN, and mTOR mRNA overexpressed in CD34+ CD38- CD47+ cells were performed by real-time quantitative transcriptase-polymerase chain reaction. Phagocytic capacity of macrophages was measured with carboxyfluorescein succinimidyl ester and fluorescent microspheres. Sorted CD34+ CD38- CD47+ cells were injected into NOD-Prkdcscid Il2rgnull mice.
Results:
The expression of CD47 on CD34+ CD38- cells of the patients in high-risk MDS based on IPSS-R/WPSS score was higher than that in low-risk MDS and controls. The signaling pathway of PI3K/AKT/mTOR is active in CD34+ CD38- CD47+ cells of MDS patients. CD47 overexpressing CD34+ CD38- cells has antiphagocytosis. CD47 overexpressing leukemia stem cell (LSC) -transplanted mice has a short survival time. The macrophages originated from MDS might elicit a pro-tumor response in MDS by inhibiting phagocytosis.
Conclusions:
Phagocytosis checkpoints are impaired in MDS. High expression of CD47 on CD34+CD38- cells indicates poor clinical prognosis in MDS.
Insights
High CD47 expression on myelodysplastic syndrome (MDS) cells impairs phagocytosis, indicating a poor prognosis. This suggests targeting CD47 could be a therapeutic strategy for MDS.
Area of Science:
- Hematology
- Immunology
- Cancer Biology
Background:
- Myelodysplastic syndrome (MDS) is a high-risk blood disorder prone to acute myeloid leukemia transformation.
- CD47 is a key regulator of phagocytosis, but its role in MDS pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of CD47 in MDS pathogenesis.
- To determine the relationship between CD47 expression and clinical prognosis in MDS patients.
Main Methods:
- Flow cytometry was used to detect CD47 and PI3K/AKT/mTOR expression on CD34+CD38- cells.
- Quantitative PCR assessed mRNA levels of key pathway proteins.
- Macrophage phagocytic capacity was measured using fluorescence assays.
- Leukemia stem cell xenotransplantation models were established in mice.
Main Results:
- CD47 expression was significantly higher on CD34+CD38- cells in high-risk MDS patients compared to low-risk MDS and controls.
- The PI3K/AKT/mTOR pathway was active in CD34+CD38-CD47+ MDS cells.
- CD47 overexpression on MDS cells inhibited phagocytosis and led to shorter survival in transplanted mice.
- MDS-derived macrophages exhibited impaired phagocytosis, potentially promoting tumor growth.
Conclusions:
- Phagocytosis checkpoints are dysregulated in MDS.
- Elevated CD47 expression on CD34+CD38- cells is a biomarker for poor prognosis in MDS.
Related Concept Videos
01:01Regulation of Hematopoietic Stem Cells
01:15Differentiation of Common Myeloid Progenitor Cells
01:19Multipotency of Hematopoietic Stem Cells