Acute myeloid leukaemia (AML) - cancer of the myeloid line of white blood cells is the most common acute leukemia affecting adults and its incidence increases with age. In 1994 Tsvee Lapidot, who worked in John Dick’s lab at the University of Toronto proposed that human acute myeloid leukaemia (AML) could arise from small populations of leukaemia-initiating (stem) cells (LSC). It was a new view on theory of human leukemogenesis.

This scheme shows importance of LSC in leukemia.

Xenogeneic hematopoietic cell transplantation - is the most reliable model for study human hematopoiesis in vivo. A few mice models with weak T-cell immunity were designed in the past, which don’t reject human cells. Dick’s group used NOD/SCID immunodeficient mice for human LSC transplantation. Other xeno-models (such as: CB17/SCID and NOD/SCID/beta2m-null) were used by different groups to study development of human leukemias and engraftment of hematopoietic stem cells. However, these immunodeficient mice had short life spans and age-dependent leakiness of humoral immunity, which made long-term evaluation of human AML in xenogenic models difficult.

Fumihiko Ishikawa at the RIKEN Research Center for Allergy and Immunology (Japan) and colleagues created a new improved longer-lived mouse model for study human leukemogenesis - NOD/SCID/IL2gamma-null (NOG). Unlike other models, these mice are less likely to reject human cells and have more efficient long-term engraftment of leukemia stem cells.

This improved model showed that only 1000 LSC, isolated from human AML samples, were/are able exclusively recapitulate disease. Unlike other “non-stem” cell population, isolated from the same samples, LSC retain self-renewal capacity in vivo over one year, demonstrated by serial transplantation experiments.

Because normal hematopoiesis during AML progression in NOG mice was inhibited like in humans, the authors proposed that it may be the result of competition for the shared bone-marrow microenvironmental niche for LSC and normal hematopoietic stem cells. A very elegant experiment showed that LSCs home to and engraft within the endosteal niche of the bone marrow, which is protecting them from chemotherapy-induced apoptosis.

A few very important conclusions arise from this great study:

- Described xenogeneic mouse model (NOG) is currently the best in vivo system to study human hematopoiesis and leukemogenesis.

- LSCs with a particular phenotype (hCD34+hCD38-) derived from human AML samples are shown to: have the ability for long-term engraftment, maintain self-renew capacity, gene expression profile and in the same time exclusively reproduce human AML during one year of serial transplantation experiment.

- LSCs home to the endosteal niche of the bone marrow, win “engraftment competition” with normal hematopoietic stem cells and rest in G0 cell cycle phase. More likely this mechanism explains why LSCs are chemotherapeutically resistant and cause AML relapse.

- Identification of leukemic stem cell niche and understanding mechanisms of their homing, engraftment and seeding could be very promising for new anti-leukemic drug development, precisely targeting LSCs or the leukemic niche.

Results of this work was published in the November issue of Nature Biotechnology.
Nat Biotechnol 2007; 25: 1315 - 1321 | doi:10.1038/nbt1350
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by Nature Reports Stem Cells: Leukemia might elbow out blood makers