The Philadelphia chromosome t(9;22)(q34;q11) in CML generates the BCR-ABL1 fusion oncogene. The mechanism by which BCR-ABL1 drives leukemogenesis is:

• A Loss of tumor suppressor function causing inability to repair DNA damage
• B Constitutive activation of tyrosine kinase activity promoting cell survival and proliferation ✓
• C Amplification of RAS signaling through guanine nucleotide exchange factors
• D Inhibition of topoisomerase II leading to chromosomal instability

Explanation

BCR-ABL1 encodes a constitutively active tyrosine kinase that continuously phosphorylates substrates involved in cell survival (PI3K-AKT), proliferation (RAS-MAPK), and inhibition of apoptosis. Unlike normal ABL1, BCR-ABL1 is not subject to allosteric autoinhibition. This is the target of imatinib and subsequent tyrosine kinase inhibitors.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.