BCRABLmediated

BCR-ABL-mediated refers to the cellular and molecular effects driven by the BCR-ABL fusion oncoprotein, a constitutively active tyrosine kinase produced by the reciprocal t(9;22)(q34;q11) Philadelphia chromosome translocation. The fusion protein arises from the juxtaposition of the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9, most notably in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (ALL). Detection of BCR-ABL transcripts or protein is a key diagnostic and monitorable feature in affected patients.

The BCR-ABL kinase drives oncogenesis by activating multiple downstream signaling pathways independent of external growth signals. Prominent pathways include the JAK/STAT, RAS/RAF/MEK/ERK, and PI3K/AKT cascades, which promote cell proliferation, survival, and resistance to apoptosis. BCR-ABL also influences cytoskeletal organization and cell adhesion, contributing to altered cell migration and interaction with the bone marrow microenvironment. In some contexts, BCR-ABL signaling increases reactive oxygen species and can affect DNA damage response and genomic stability, further supporting leukemogenesis.

Clinical relevance and treatment focus on BCR-ABL-mediated pathology. Tyrosine kinase inhibitors (TKIs) targeting the ABL kinase, such as imatinib, vastly improved outcomes in CML and selected ALL cases. Resistance can develop through mutations in the BCR-ABL kinase domain (with T315I among the well-known examples), prompting escalation to second- and third-generation TKIs (dasatinib, nilotinib, bosutinib, ponatinib). Monitoring of BCR-ABL levels by molecular assays guides treatment decisions and response assessment.