Targeting beta2-microglobulin for induction of tumor apoptosis in human hematological malignancies.
We discovered that monoclonal antibodies (mAbs) specific to human beta(2)-microglobulin (beta(2)M) induce apoptosis in vitro and were therapeutic in mouse models of myeloma and other hematological tumor cells. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms. The mAbs induced cell death via recruiting MHC class I molecules to lipid rafts and activating Lyn and PLCgamma2, leading to activated JNK and inhibited PI3K/Akt and ERK, compromised mitochondrial integrity, and caspase-9-dependent cascade activation. Although the expression of beta(2)M on normal hematopoietic cells is a potential safety concern, the mAbs were selective to tumor-transformed cells and did not induce apoptosis of normal cells. Therefore, such mAbs offer the potential for a therapeutic approach to hematological malignancies.
Yang
Jing
J
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Qian
Jianfei
J
Wezeman
Michele
M
Wang
Siqing
S
Lin
Pei
P
Wang
Michael
M
Yaccoby
Shmuel
S
Kwak
Larry W
LW
Barlogie
Bart
B
Yi
Qing
Q
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D053453:Caspase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D051057:Proto-Oncogene Proteins c-akt; D001613:beta 2-Microglobulin; D019061:src-Family Kinases; C060902:lyn protein-tyrosine kinase