Jackson Laboratory's Leonard Shultz PhD Helps Develop a Better Leukemia Mouse Model
Dr. Leonard Shultz of The Jackson Laboratory and 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 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)
Dr. Shultz and his team intravenously injected primary human LS cells into newborns of this strain and found that they have long-term engraftment and differentiation capacity, exclusively recapitulate AML and retain 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 differentiate into AML cancer cells, but others remain quiescent - do 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.
Therapies for leukemia and other cancers are improving all the time, but cancer is a complicated and adaptable foe. Better models are needed to study its pathogenesis and to develop more effective treatments and, better yet, preventions and cures. The AML xenograft model developed by Dr. Shultz and his collaborators promises to be such a model.
(Author in bold is a Jackson Laboratory Professor)
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.