期刊
BLOOD
卷 126, 期 12, 页码 1433-1442出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-01-624833
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资金
- National Science Foundation for Young Scholars of China [81300415]
- National Natural Science Funds for Distinguished Young Scholar [81025011]
- National Natural Science Foundation of China [81230052, 81090414]
To design an effective antibody therapy to improve clinical outcomes in leukemia, the identification of novel cell surface antigens is needed. Herein, we demonstrate a role for transmembrane tumor necrosis factor-alpha (tmTNF-alpha) in leukemia. To characterize tmTNF-alpha expression in acute leukemia (AL), normal hematopoietic cells, and nonhematopoietic tissues, we used a monoclonal antibody, termed C1, which specifically recognizes the tmTNF-alpha domain. We found that tmTNF-alpha was preferentially expressed by AL and leukemia stem cells (LSCs). More abundant expression correlated with poor risk stratification, extramedullary infiltration, and adverse clinical parameters. Moreover, knockdown of tmTNF-alpha(+) expression rendered leukemia cells more sensitive to chemotherapy in vitro and delayed regeneration of leukemia in NOD-SCID mice. Targeting tmTNF-alpha by C1 resulted in leukemia cell killing via antibody-dependent cell-mediated and complement-dependent cytotoxicity in vitro and inhibited leukemia cell growth in vivo while simultaneously sparing normal hematopoietic cells. Notably, C1 administration impaired the regeneration of leukemia in secondary serial transplantation into NOD-SCID mice. In conclusion, tmTNF-alpha has a favorable AL- and LSC-associated expression profile and is important for the survival and proliferation of these cells. C1-mediated targeting shows potent anti-LSC activity, indicating that tmTNF-alpha represents a novel target antigen in AL.
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