## Why "Constitutively active tyrosine kinase driving unregulated proliferation via RAS/RAF/MEK/ERK, JAK-STAT, and PI3K/AKT pathways" is right The two fusion signals marked **A** in the FISH diagram represent the BCR-ABL1 fusion oncogene on the Philadelphia chromosome (derivative chromosome 22), arising from the t(9;22)(q34;q11) translocation. The BCR-ABL1 fusion protein (typically p210 in CML) is a constitutively active tyrosine kinase that drives unregulated cell proliferation through activation of RAS/RAF/MEK/ERK, JAK-STAT, and PI3K/AKT signaling pathways. This is the defining pathogenic mechanism of CML and the basis for TKI therapy. (Harrison's Principles of Internal Medicine 21e, Chapter 102; Robbins Basic Pathology 10e) ## Why each distractor is wrong - **Loss of tumor suppressor function due to deletion of chromosome 22q**: CML is driven by a gain-of-function translocation creating an oncogene, not loss of a tumor suppressor. The BCR-ABL1 fusion is constitutively active, not a loss of function. - **Increased expression of normal ABL1 protein from chromosome 9**: Normal ABL1 expression is tightly regulated and not pathogenic. The pathology arises specifically from the fusion protein's constitutive kinase activity, not from increased normal ABL1. - **Impaired DNA repair leading to accumulation of random mutations**: While secondary mutations (e.g., T315I) can develop during disease progression, the primary pathogenic mechanism of CML is the BCR-ABL1 fusion kinase itself, not a primary DNA repair defect. **High-Yield:** BCR-ABL1 fusion = constitutively active tyrosine kinase = CML pathogenesis; FISH detects the fusion; TKIs block the kinase activity. [cite: Harrison's Principles of Internal Medicine 21e, Chapter 102 (CML); Robbins Basic Pathology 10e]
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