Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events.
BACKGROUND
Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Hani
H
Kim
Lisa C
LC
Gillis
Jordan D
JD
Jarvis
Stuart
S
Yang
Kai
K
Huang
Sandy
S
Der
Dwayne L
DL
Barber
D001549:Benzamides; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D014178:Translocation, Genetic; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C120888:TEL-PDGFRbeta fusion protein, human