General information on BCR-ABL1 protein
BCR-ABL1 is encoded by the BCR-ABL1 fusion gene that results from the genetic material of both chromosome 9 and chromosome 22. The ABL1 gene located on chromosome 9 is juxtaposed onto the breakpoint cluster region of BCR gene which is located on chromosome 22. As such BCR-ABL1 is a hybrid protein and a tyrosine kinase. The protein fusion interrupts the genome stability and causes the cell to divide uncontrollably. The BCR-ABL1 protein complex also impairs a different signaling pathway that regulates the cell cycle.
nBCR-ABL1 protein is phosphorylated by JAK2 protein at Y177. Upon phosphorylation, BCR-ABL1 fusion protein is stabilized which strengthens its tumorigenic cell signaling. JAK2 protein mutations has been linked to aberrant BCR-ABL1 protein activity. JAk/ BCR-ABL1 abnormalities have been involved in increase survival and proliferation of myelogenous leukemia cells and hematologic malignancies. BCR-ABL1 protein complex upregulates JAK-STAT signaling and helps maintain leukemic cell division and growth. For this reason, both JA2 protein and BCR-ABL1 protein have been targets for anti-cancer treatments.
nBCR-ABL protein also activates the Ras/MAPK/ERK pathway. The latter consists of a chain of proteins located on the cell surface that communicate the signal from a receptor on the surface to the nucleus of the cell. This leads to gene transcriptions that results in increased cell proliferation. Ras/MAPK/ERK pathway also increases expression levels of osteopontin (OPN) which indirectly increases the proliferation of leukemic cells. BCR-ABL has also been implicated to higher levels of activated Ras bound to GTP which inhibits cell induced apoptosis. The BCR-ABL induced apoptotic inhibition is resistant to drug-induced apoptosis. The expression levels of pro-apoptotic molecules such as p53, p21 and Bax is increased. However, their activity is impaired, and apoptosis is not carried out. Furthermore, BCR-ABL fusion protein prevent caspase 9 and caspase 3 activity. Both of these proteins are required for efficient apoptosis. Their inhibition further strengthens BCR-ABL fusion protein anti-apoptotic activity.