Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells without the loss of their capability to differentiate. CML is derived from the hematopoietic stem cells (1) with the Philadelphia chromosome resulting from of a reciprocal translocation between the chromosomes 9 and 22 t(9;22)-(q34;q11). This translocation produces a fusion gene known as BCR-ABL which acquires uncontrolled tyrosine kinase activity, constantly turning on its downstream signaling molecules/pathways, and promoting proliferation of leukemia cell through anti-apoptosis and acquisition of additional mutations. To evaluate the role of each critical downstream signaling molecule of BCR-ABL and test therapeutic drugs in vivo, it is important to use physiological mouse disease models. In this chapter, we describe a mouse model of CML induced by BCR-ABL retrovirus (MSCV-BCR-ABL-GFP; MIG-BCR-ABL) and how to use this model in translational research.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ren, R. (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5, 172–183.
Wang, J. C., Lapidot, T., Cashman, J. D., Doedens, M., Addy, L., Sutherland, D. R., et al. (1998) High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 91, 2406–2414.
Nowell, P. C. and Hungerford, D. A. (1960) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25, 85–109.
Rowley, J. D. (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293.
Groffen, J., Stephenson, J. R., Heisterkamp, N., de Klein, A., Bartram, C. R. and Grosveld, G. (1984) Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36, 93–99.
Wong, S. and Witte, O. N. (2004) The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22, 247–306.
Deininger, M. W., Goldman, J. M. and Melo, J. V. (2000) The molecular biology of chronic myeloid leukemia. Blood 96, 3343–3356.
Hariharan, I. K., Harris, A. W., Crawford, M., Abud, H., Webb, E., Cory, S., et al. (1989) A bcr-v-abl oncogene induces lymphomas in transgenic mice. Mol Cell Biol 9, 2798–2805.
Heisterkamp, N., Jenster, G., Kioussis, D., Pattengale, P. K. and Groffen, J. (1991) Human bcr-abl gene has a lethal effect on embryogenesis. Transgenic Res 1, 45–53.
Castellanos, A., Pintado, B., Weruaga, E., Arevalo, R., Lopez, A., Orfao, A., et al. (1997) A BCR-ABL(p190) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. Blood 90, 2168–2174.
Inokuchi, K., Dan, K., Takatori, M., Takahuji, H., Uchida, N., Inami, M., et al. (2003) Myeloproliferative disease in transgenic mice expressing P230 Bcr/Abl: longer disease latency, thrombocytosis, and mild leukocytosis. Blood 102, 320–323.
Daley, G. Q., Van Etten, R. A. and Baltimore, D. (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830.
Kelliher, M. A., McLaughlin, J., Witte, O. N. and Rosenberg, N. (1990) Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A 87, 6649–6653.
Li, S., Ilaria, R. L., Jr., Million, R. P., Daley, G. Q. and Van Etten, R. A. (1999) The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 189, 1399–1412.
Hu, Y., Liu, Y., Pelletier, S., Buchdunger, E., Warmuth, M., Fabbro, D., et al. (2004) Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 36, 453–461.
Peng, C., Brain, J., Hu, Y., Goodrich, A., Kong, L., Grayzel, D., et al. (2007) Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells. Blood 110, 678–685.
Hu, Y., Swerdlow, S., Duffy, T. M., Weinmann, R., Lee, F. Y. and Li, S. (2006) Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A 103, 16870–16875.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Humana Press, a part of Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Peng, C., Li, S. (2010). CML Mouse Model in Translational Research. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 602. Humana Press. https://doi.org/10.1007/978-1-60761-058-8_15
Download citation
DOI: https://doi.org/10.1007/978-1-60761-058-8_15
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60761-057-1
Online ISBN: 978-1-60761-058-8
eBook Packages: Springer Protocols