JAX Notes March 01, 2008

Jackson Laboratory's Professor Helps Develop a Better in vivo model for AML Leukemia

Leonard Shultz, Ph.D., of The Jackson Laboratory, along with collaborators at Harvard Medical School and several Japanese institutions (including the RIKEN Research Center for Allergy and Immunology) have significantly increased our understanding of and moved the medical field closer to a cure for human myelogenous leukemia (AML) (Ishikawa et al. 2007).

The most common adult leukemia, AML is characterized by the clonal expansion of immature myeloblasts from leukemic stem (LS) cells, which belong to a rare, recently discovered, and little understood group of cancer stem cells. Although AML can generally be forced into remission by chemotherapy, 15% of the cancers don't respond to the initial treatment, and 70% of them relapse. Recent research indicates that LS cells may be responsible for this high incidence of AML cancer recurrence.

The NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557)
mouse used by Shultz and his colleagues.

To understand how human LS cells function, the research team developed a primary human (patient-derived) AML xenotransplantation model using newborn mice of the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557) strain, a strain developed by Shultz (Shultz et al. 2005). The strain's unique features include severe combined immune deficiency (scid), resistance to lymphoma (and therefore a longer lifespan) and superior engraftment of human tissues, including cancer cells. The strain's longevity, over 16 months, is particularly important because it allows researchers to conduct long-term experiments not possible with other immunodeficient mice.

Dr. Shultz and his team intravenously injected primary human LS cells into newborns of this strain. They discovered that the strain has long-term engraftment and differentiation capacity. It exclusively recapitulates AML and retains self-renewal capacity in vivo, providing a very representative model of human AML. The LS cells homed to and engrafted within the osteoblast-rich area of the bone marrow. There, some differentiated into AML cancer cells, but others remained quiescent: that is, they did not progress through the cell cycle and multiply. Their quiescence may explain why human LS cells are resistant to the cytotoxic effects of chemotherapy, which target fast-dividing cells.

Not surprisingly, but for reasons that are not understood, the research team found that LS cells are indeed highly resistant to conventional chemotherapy. With this knowledge in hand, scientists may be able to use the NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mouse to develop AML therapies specifically targeted to LS cells.

Based on this research, The Jackson Laboratory is expanding its collection of Patient-derived xenograft models including models for Acute myeloid leukemia (AML), that are available to the public.

Therapies for leukemia and other cancers are improving all the time, but cancer is a complicated and adaptable foe. Patient-derived models are valuable tools to study its pathogenesis and to develop more effective treatments and, better yet, preventions and cures.

References

Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD. 2007. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25:1315-21.

Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R. 2005. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells. J Immunol 15:6477-89.