Philadelphia (Ph)- chromosome positive leukemias are relatively common and have a poor prognosis. The Ph-chromosome is generated by a reciprocal t(9;22) translocation, which fuses the ABL and BCR genes from chromosomes 9 and 22. P190 and P210 are BCR/ABL fusion proteins made on the Ph-chromosome, and are the direct cause of leukemia. Mouse models for this type of human leukemia are valuable for studying possible methods of treatment, early stages of the disease, and exploring the signalling pathways which lead to tumorigenesis in vivo. In the previous period of grant support the investigator generated and characterized P210 and P190 BCR/ABL transgenic mice, and, in addition, bcr -/- mice. The current proposal builds on the data and strains previously generated to address specific gaps in our knowledge concerning the pathobiology of and mechanism of transformation by BCR/ABL in vivo. Specifically, Dr. Heistercamp postulates that activity of the ABL/BCR reciprocal translocation product influences the development of leukemia associated with P210. To test this, she will assess biological activity of ABL/BCR in vivo on hematopoiesis and compare leukemogenesis in P210 ABL/BCR + BCR/ABL with that in P210 BCR/ABL transgenic mice. How BCR/ABL causes leukemia is of obvious interest and recent experiments have shown the interaction of a large number of proteins with BCR/ABL in vivo. They intend to test the biological relevance of such interactions to human Ph-positive leukemia in vivo. They will examine if the normal bcr protein influences leukemogenesis and if so, by which mechanism, in BCR/ABL P190 transgenic mice lacking the endogenous bcr gene. They have identified Crkl, an SH2-SH3 adaptor protein, as a substrate for BCR/ABL with clear relevance to Ph- positive leukemia in man: Crkl is specifically tyrosine-phosphorylated only in patient material expressing BCR/ABL. Is crkl required for BCR/ABL mediated tumorigenesis and if so, through which mechanism? This will be studied in crkl -/- and CRKL x BCR/ABL P190 transgenics. Is leukemogenesis caused by BCR/ABL mediated through interaction of signalling molecules such as Grb-2 with phosphorylated tyrosine residue 177 encoded by BCR exon 1? This will be examined in P190 BCR/ABL transgenic mice, in which tyrosine residue 177 of BCR exon 1 has been mutated. They will study if and how interactions with the cytoskeleton, through the actin-binding domain of Abl, are important for the development of BCR/ABL associated leukemia in vivo, in mice transgenic for BCR/ABL P190 which lacks the actin-binding domain of ABL. These experiments will result in the identification of signalling pathways which transduce the transforming signal of BCR/ABL, an important step towards the ultimate goal of developing methods of treatment for Ph-positive leukemias.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050248-06
Application #
2608058
Study Section
Pathology B Study Section (PTHB)
Program Officer
Shen, Grace L
Project Start
1991-09-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Zhang, B; Groffen, J; Heisterkamp, N (2007) Increased resistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblastic leukemia cells. Leukemia 21:1189-97
Cho, Young Jin; Zhang, Bin; Kaartinen, Vesa et al. (2005) Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol 25:5777-85
Cho, Young Jin; Hemmeryckx, Bianca; Groffen, John et al. (2005) Interaction of Bcr/Abl with C3G, an exchange factor for the small GTPase Rap1, through the adapter protein Crkl. Biochem Biophys Res Commun 333:1276-83
Mishra, S; Zhang, B; Groffen, J et al. (2004) A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. Leukemia 18:23-8
Curtis, Christina; Hemmeryckx, Bianca; Haataja, Leena et al. (2004) Scambio, a novel guanine nucleotide exchange factor for Rho. Mol Cancer 3:10
Mishra, Suparna; Reichert, Anja; Cunnick, Jess et al. (2003) Protein kinase CKIIalpha interacts with the Bcr moiety of Bcr/Abl and mediates proliferation of Bcr/Abl-expressing cells. Oncogene 22:8255-62
Kaartinen, Vesa; Nagy, Andre; Gonzalez-Gomez, Ignacio et al. (2002) Vestibular dysgenesis in mice lacking Abr and Bcr Cdc42/RacGAPs. Dev Dyn 223:517-25
Heisterkamp, Nora; Groffen, John (2002) Philadelphia-positive leukemia: a personal perspective. Oncogene 21:8536-40
Hemmeryckx, Bianca; Reichert, Anja; Watanabe, Meguru et al. (2002) BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl. Oncogene 21:3225-31
Reichert, A; Heisterkamp, N; Daley, G Q et al. (2001) Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood 97:1399-403

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