A cell initiating human acute myeloid leukaemia after transplantation into SCID mice

Abstract

Most human acute myeloid leukaemia (AML) cells have limited proliferative capacity, suggesting that the leukaemic clone may be maintained by a rare population of stem cells. This putative leukaemic stem cell has not been characterized because the available in vitro assays can only detect progenitors with limited proliferative and replating potential. We have now identified an AML-initiating cell by transplantation into severe combined immune-deficient (SCID) mice. These cells homed to the bone marrow and proliferated extensively in response to in vivo cytokine treatment, resulting in a pattern of dissemination and leukaemic cell morphology similar to that seen in the original patients. Limiting dilution analysis showed that the frequency of these leukaemia-initiating cells in the peripheral blood of AML patients was one engraftment unit in 250,000 cells. We fractionated AML cells on the basis of cell-surface-marker expression and found that the leukaemia-initiating cells that could engraft SCID mice to produce large numbers of colony-forming progenitors were CD34+ CD38-; however, the CD34+ CD38+ and CD34- fractions contained no cells with these properties. This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.

Telomere and telomerase in stem cells

“…The first evidence that a rare population of stem cells maintain the human cancer came from a study on haematopoietic malignancies (Lapidot et al, 1994). Haematopoietic malignancies can be divided into premalignant, chronic, and acute stages, the last being the most advanced and malignant.…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…Consequently, McCulloch and colleagues postulated that AML can be considered as a clonal hemopathy [22,23]. However, the first prospective identification, characterization, and isolation of CSC/CICs was performed years later in AML on the basis of their phenotypical similarities to normal hematopoietic stem cells [24]; in their innovative work, Dick and colleagues have identified CD34 + CD38 − cells as AML CSCs [24,25]. Subsequently, the group reported that only CD34 + CD38 − cells were able to reproduce AML in recipient immunodeficient mice, which closely resembled the original patient's disease, and exhibited its full heterogeneous phenotype.…”

CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

“…To date, the existence of CSCs has been proven in the context of many cancers, including those of leukemia, breast cancer, glioblastoma, prostate cancer, pancreatic cancer and colon cancer (Lapidot et al, 1994;Bonnet and Dick, 1997;Al-Hajj et al, 2003;Hemmati et al, 2003;Singh et al, 2003Singh et al, , 2004Collins et al, 2005;Ponti et al, 2005;Haraguchi et al, 2006;Patrawala et al, 2006;Li et al, 2007;O'Brien et al, 2007;Ricci-Vitiani et al, 2007). Recently, we have determined that HCC is hierarchically organized and originates from a primitive stem/progenitor group of cells for which CD133 þ precursors constitute one of the most immature stage (Ma et al, 2007).…”