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Pathway Description
BCR-ABL Action in CML Pathogenesis
Homo sapiens
Disease Pathway
Created: 2017-07-28
Last Updated: 2019-08-16
The BCR-ABL fusion protein is a cytoplasm-targeted constitutively active tyrosine kinase that causes uninhibited cell proliferation via signalling cascades. This fusion protein is the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. The action of BCR-ABL produces chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. Physiologically, ABL is a tyrosine kinase involved with cell growth that moves between the nucleus and the cytoplasm. Upon fusion with BCR, the oncoprotein is constitutively activated due to a preference for dimerization or tetramerization promoting subsequent autophosphorylation, and it is retained in the cytoplasm. BCR-ABL activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. BCR-ABL forms a complex with GRB2, GAB2, and SOS that activates Ras (converted from its inactive GDP-bound state to the active GTP-bound state). Ras signalling triggers the MAPK/ERK pathway which stimulates abnormal cell proliferation through regulation of transcription and translation. The BCR-ABL/GRB2/GAB2/SOS complex also activates STAT5 either through direct phosphorylation or indirectly through JAK2 kinase to promote survival. Additionally, JAK2 kinase activates the MYC transcription factor for growth-related genes. The PI3K/Akt pathway can be activated either via the BCR-ABL/GRB2/GAB2/SOS complex or the BCR-ABL/CRK/CRKL/CBL/PI3K complex. Akt functions in: (1) increasing cell proliferation by promoting the degradation of p27 (CDKN1B) through the upregulation of SKP2; (2) enhancing protein translation (and subsequently increasing cell proliferation) by activating mTOR kinase; (3) and preventing apoptosis to ensure survival by inhibiting both FOXO transcription factors and the protein Bcl2-associated agonist of cell death (BAD) as well as activating MDM2 which inhibits the tumour suppressor p53.
References
BCR-ABL Action in CML Pathogenesis References
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