Japanese and American researchers have used a mouse model engrafted with human cells to characterize a population of cancerous stem cells that gives rise to acute myelogenous leukemia (AML)1.
The cells are haematopoietic stem cells, a subset of bone marrow-derived cells that gives rise to essentially all of the cell types in the blood and immune systems. When isolated from patients with AML the cells are called leukemic stem (LS) cells, and produce the immature leukemic cells characteristic of this disease.
The team, based at the RIKEN Research Center for Allergy and Immunology in Yokohama, developed the mouse model to better study the pathogenic mechanisms leading to the development of human leukemia. The model uses as recipients a strain of mice with a severe immunodeficiency that have been further compromised by a mutation that inactivates a major subset of the immune system’s signaling molecules. These mice cannot recognize human cells as ’non-self’ and by using newborn mice for the engraftment of the human cells, a more robust and longer-lived model is created.
Initially, the researchers demonstrated that engrafted human LS cells homed to the bone marrow and that these cells were capable of both self-renewal and differentiation into non-stem leukemic cells.
Antibody staining of bone sections showed that the LS cells specifically homed to and engrafted within the micro-environmental niche at the endosteum, a layer of connective tissue on the inner surface of the bone cavity. The presence of the LS cells suppressed normal formation of new blood cells, a phenomenon also observed in AML patients.
In addition, the LS cells were resistant to the cytotoxic agent Ara-C, due to the majority of them being in the quiescent (G0) phase of the cell cycle. The researchers believe this explains why AML relapse after chemotherapy is common—non-stem leukemic cells, but not LS cells, are eliminated by cell cycle-dependent cytotoxic agents used to treat the disease (Fig. 1).
Finally, genetic analysis of the engrafted LS cells showed they retained characteristic gene expression patterns, even after serial transplantation.
According to principal investigator Fumihiko Ishikawa, the retention of phenotype, function and gene expression means the model will be a useful tool.
“This xenotransplant model will be helpful for developing a cell-bank for human primary AML stem cells and for testing safety and efficacy of various treatment modalities for AML,” he notes. “It has enabled us to identify the major reason and mechanism for AML relapse.”
Reference
1. Ishikawa, F., Yoshida, S., Saito, Y., Hijikata, A., Kitamura, H., Tanaka, S., Nakamura, R., Tanaka, T., Tomiyama, H., Saito, N., et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nature Biotechnology 25, 1315–1321 (2007).
