Chronic myeloid leukemia is caused by a balanced chromosomal translocation resulting in the formation of BCR-ABL1 fusion gene encoding a constitutively active BCR-ABL1 tyrosine kinase, which activates multiple signal transduction pathways leading to malignant transformation.
The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML).
Thus, further dissection of the regulatory networks that drive BCR-ABL-induced malignant transformation may help to identify other novel therapeutic approaches that complement TKI treatment.
Imatinib was designed on the basis of the structure of the ATP binding site of the Abl protein kinase with the aim to stabilizes the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in chronic myelogenous leukemia (CML).
The expression of the chimeric BCR/ABL1 fusion gene resulting from t(9;22)(q34;q11) in chronic myelogenous leukemia (CML) is necessary for malignant transformation, but not sufficient to maintain disease progression.
We conclude that BCR-ABL PTK activity drives the expression of specific target genes that contribute to the malignant transformation of Ph-positive cells.
Although several oncogenes have been identified through the study of tumor-producing retroviruses in animals, discovery of the BCR/ABL translocation, the altered 8.5 kb BCR/ABL transcript, and the hybrid BCR/ABL P210 protein with enhanced tyrosine kinase activity has provided one of the first examples of a human neoplasm in which structural alterations in a normal cellular gene might lead to malignant transformation.
These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.