A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9.
Blast-Crisis, Bone-Marrow-Cells, Bone-Marrow-Transplantation, Cell-Division, Cloning-Molecular, Disease-Models-Animal, Disease-Progression, Fusion-Proteins-bcr-abl, Green-Fluorescent-Proteins, Homeodomain-Proteins, Humans, Leukemia-Myeloid-Chronic, Luminescent-Proteins, Nuclear-Pore-Complex-Proteins, Oncogene-Proteins-Fusion, Piperazines, Proviruses, Pyrimidines, Tumor-Cells-Cultured
Proc Natl Acad Sci U S A 2002 May; 97(11):7622-7.
Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.
Dash, A B.; Williams, I R.; Kutok, J L.; Tomasson, M H.; Anastasiadou, E; Lindahl, K; Li, S; Van, E t.; Borrow, J; Housman, D; Druker, B; and Gilliland, D G., "A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9." (2002). Faculty Research 2000 - 2009. 879.