Oncogenic Tyrosine Kinases Regulate Proliferative and Survival Signals through Activation of Id1.

The oncogenic tyrosine kinases, such as BCR-ABL, TEL-ABL, TEL-PDGFbR and FLT3-ITD, play a major role in the development of hematopoietic malignancy. They activate many of the same signal transduction pathways, including the RAS/MAPK pathway, STAT/JAK pathway and PI3-K/AKT pathway. Although activation of signal transduction pathway has been extensively studied, few bone fide target genes have been identified. To identify the critical target genes that are required for transformation in hematopoietic cells, specific tyrosine kinase inhibitors were applied to 32Dcl3 cells expressing various activated tyrosine kinases. Using Affymetrix oligonucleotide arrays, we have identified inhibitor of DNA binding 1 (Id1), which is involved in development, cell cycle and tumorigenesis, as a common target gene of oncogenic tyrosine kinases. To characterize the biological consequence of Id1 expression, we inhibited the expression of Id1 in two human leukemia cell lines (Molm-14 and K562) by an antisense Id1 construct. In both cell lines, we observed a growth inhibition associated with release of inhibition of p27^Kip. In addition, inactivation of Id1 sensitized K562 cells to Trail-induced apoptosis. Our findings suggest that Id1 is an important target of constitutively activated tyrosine kinases, and may be a therapeutic target for leukemias involving oncogenic tyrosine kinases.