Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events

Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions.Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen Vα1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB.Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations.Chromosomal translocations are the most frequently occurring genetic abnormalities in leukemias and they exploit a mechanism by which normal regulatory pathways are subverted, thereby providing a proliferative advantage to a leukemic clone. Many of the chromosomal translocations involve tyrosine kinases. In most cases, translocations juxtapose a tyrosine kinase domain to another protein containing an oligomerization motif. For example, BCR-ABL is generated by t(9;22)(q34;q11) [1], which fuses the N-terminus of BCR to the C-terminus of ABL. TEL-PDGFRB (t(5;12)(q33;p13)) [2] and TEL-JAK2 (t(9;12)(p24;p13)) [3,4] fuse the N-terminus of TEL to the C-terminus of PDGFRB or JAK2, respectively. In all th