TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells.
Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Here we identified T cell immunoglobulin mucin-3 (TIM-3) as a surface molecule expressed on LSCs in most types of AML except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). TIM-3(+) but not TIM-3⁻ AML cells reconstituted human AML in immunodeficient mice, suggesting that the TIM-3(+) population contains most, if not all, of functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden and eliminated LSCs capable of reconstituting human AML in secondary recipients. These data suggest that TIM-3 is one of the promising targets to eradicate AML LSCs.
Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
Yoshikane
Y
Kikushige
Takahiro
T
Shima
Shin-ichiro
S
Takayanagi
Shingo
S
Urata
Toshihiro
T
Miyamoto
Hiromi
H
Iwasaki
Katsuto
K
Takenaka
Takanori
T
Teshima
Toshiyuki
T
Tanaka
Yoshimasa
Y
Inagaki
Koichi
K
Akashi
D000328:Adult; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D019070:Cell Lineage; D006410:Hematopoiesis; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014183:Transplantation, Heterologous
D000906:Antibodies; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007074:Immunoglobulin G; D008565:Membrane Proteins