TIM-3 Is a Promising Target to Selectively Kill Acute Myeloid Leukemia Stem Cells

• Published in: Cell stem cell 2010-12, Vol.7 (6), p.708-717
• Main Authors: Kikushige, Yoshikane, Shima, Takahiro, Takayanagi, Shin-ichiro, Urata, Shingo, Miyamoto, Toshihiro, Iwasaki, Hiromi, Takenaka, Katsuto, Teshima, Takanori, Tanaka, Toshiyuki, Inagaki, Yoshimasa, Akashi, Koichi
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibodies - therapeutic use; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell Lineage; Cell physiology; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Hematopoiesis; Hepatitis A Virus Cellular Receptor 2; Humans; Immunoglobulin G - immunology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Molecular and cellular biology; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Transplantation, Heterologous
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2010.11.014

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. ► TIM-3 is highly expressed in stem cells in AML of most FAB types except for M3 ► TIM-3 is not expressed in normal hematopoietic stem cells ► TIM-3 killing antibody treatment could eradicate human AML in a xenograft model ► Targeting TIM-3 could be a practical approach for human AML treatment