Authors: Hao Qian, Lijuan Xia, Peixue Ling, Samuel Waxman and Yongkui Jing

Hao Qian

The Division of Hematology/Oncology; Department of Medicine; The Tisch Cancer Institute; Mount Sinai School of Medicine; New York, NY USA; School of Pharmaceutical Sciences; Shandong University; Jinan, China

Lijuan Xia

The Division of Hematology/Oncology; Department of Medicine; The Tisch Cancer Institute; Mount Sinai School of Medicine; New York, NY USA

Peixue Ling

Shangdong Biochemical Institute; Jinan, China

Samuel Waxman

The Division of Hematology/Oncology; Department of Medicine; The Tisch Cancer Institute; Mount Sinai School of Medicine; New York, NY USA

Yongkui Jing

Corresponding author: yongkui.jing@mssm.edu
The Division of Hematology/Oncology; Department of Medicine; The Tisch Cancer Institute; Mount Sinai School of Medicine; New York, NY USA

Abstract:
CD44 is a cell surface antigen expressed on acute myeloid leukemia cells and is used as a marker to isolate leukemia stem cells. CD44 ligation with the antibody A3D8 has been found to induce apoptosis in human acute promyelocytic leukemia (APL) cells via activation of caspase-8. The mechanism of A3D8-induced caspase-8 activation was studied in APL NB4 cells. A3D8 induces lipid raft clustering which causes Fas aggregation as determined with a confocal microscope. A3D8-induced apoptosis is abrogated by the lipid raft disrupting agent methyl-β-cyclodextrin and the caspase-8 inhibitor Z-IETD-fmk. Western blot analysis reveals that A3D8 binds to the standard form of CD44 (CD44s). HL-60 cells without detectable CD44s protein are not responsive to A3D8-induced apoptosis. SKNO-1 cells containing higher level of CD44s protein are more sensitive to A3D8-induced apoptosis than NB4 cells. These results indicate that A3D8 induces apoptosis in leukemia cells through caspase-8 activation by binding to CD44s protein and inducing lipid raft clustering.

Received: April 17, 2012; Accepted: August 8, 2012; Published Online: August 16, 2012

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