The Molecular Bases of the Self-Renewal and Differentiation of Leukemic Stem Cells

Kazuhito      Naka; Masako      Ohmura; Takayuki      Hoshii; Teruyuki      Muraguchi; Atsushi      Hirao

doi:10.2174/157339408785294267

Abstract

New evidence has dramatically demonstrated that only a minority of cancer cells has the capacity to proliferate extensively and form new tumors; these cells are called “tumor-initiating cells” or “cancer stem cells”. In this review, we focus on recent molecular insights into the nature of cancer stem cells in leukemia, leukemic stem cells (LSCs). LSCs arise not only from primitive hematopoietic stem cells (HSCs) with self-renewal capacity but also from committed progenitor cells that normally lack the ability to self-renew. These latter cells gain stem cell properties by reactivating a gene expression program similar to that functioning in normal HSCs. The self-renewal and differentiation capacities of normal primitive hematopoietic cells are controlled by complex signaling pathways involving Wnt/β-catenin, Pu.1/JunB and PI3K/Akt. These same mediators also participate in the leukemogenesis. In mice, administration of drugs such as rapamycin and anti-CD44 antibody, which target properties unique to LSCs, can selectively deplete these cells in vivo. The goal for this field is to design successful human leukemia therapies based on the targeting or manipulation of features specific to LSCs.

Keywords: Leukemic stem cells, hematopoietic stem cells, self-renewal capacity

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