Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells.
Antineoplastic-Agents, Bone-Marrow-Transplantation, Cell-Cycle, Cell-Lineage, Cell-Separation, Drug-Design, Drug-Resistance-Neoplasm, Flow-Cytometry, Gene-Expression-Regulation-Leukemic, Interleukin-2-Receptor-alpha-Subunit, Leukemia, Mice-SCID, Neoplastic-Stem-Cells, Receptors-IgG, Transplantation-Heterologous
Sci Transl Med 2010 Feb; 2(17):17ra9.
Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32- or CD25-positive LSCs could initiate AML and were cell cycle-quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32- and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.
Saito, Y; Kitamura, H; Hijikata, A; Tomizawa, Murasawa M.; Tanaka, S; Ozawa, H; Wake, A; Taniguchi, S; Shultz, L D.; Ohara, O; and et, al, "Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells." (2010). Faculty Research 2010. 55.