TIM-3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways

Acute myeloid leukemia (AML) is hierarchically organized by self-renewing leukemic stem cells (LSCs). LSCs originate from hematopoietic stem cells (HSCs) by acquiring multistep leukemogenic events. To specifically eradicate LSCs, while keeping normal HSCs intact, the discrimination of LSCs from HSCs is important. We have identified T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as an LSC-specific surface molecule in human myeloid malignancies and demonstrated its essential function in maintaining the self-renewal ability of LSCs. TIM-3 has been intensively investigated as a "coinhibitory" or "immune checkpoint" molecule of T cells. However, little is known about its distinct function in T cells and myeloid malignancies. In this review, we discuss the structure of TIM-3 and its function in normal blood cells and LSCs, emphasizing the specific signaling pathways involved, as well as the therapeutic applications of TIM-3 molecules in human myeloid malignancies.