Which of the following best describes the mechanism by which the BCR-ABL fusion protein (Philadelphia chromosome) drives chronic myeloid leukemia?

Question

Accepted Answer

B. Constitutive tyrosine kinase activity causing uncontrolled proliferation. ## BCR-ABL Fusion Protein and CML Pathogenesis

**Key Point:** The BCR-ABL fusion protein is a constitutively active tyrosine kinase that drives chronic myeloid leukemia (CML) through uncontrolled phosphorylation of downstream signaling proteins, independent of growth factor stimulation.

### Philadelphia Chromosome: t(9;22) Translocation

The t(9;22) translocation juxtaposes:
- **ABL** (Abelson tyrosine kinase) from chromosome 9
- **BCR** (Breakpoint Cluster Region) from chromosome 22
- Result: **BCR-ABL** fusion gene encoding a 210 kDa protein

### Mechanism of Leukemogenesis

```mermaid
flowchart TD
  A[t 9;22 translocation] --> B[BCR-ABL fusion protein]
  B --> C[Constitutive tyrosine kinase activity]
  C --> D[Phosphorylation of downstream proteins]
  D --> E[Activation of RAS/MAPK, PI3K/AKT, JAK/STAT pathways]
  E --> F[Uncontrolled myeloid proliferation]
  E --> G[Impaired apoptosis]
  E --> H[Reduced adhesion to bone marrow stroma]
  F --> I[CML]
```

### Why BCR-ABL Drives CML

1. **Constitutive kinase activity** — BCR-ABL phosphorylates target proteins WITHOUT requiring ligand binding or growth factor stimulation
2. **Multisite phosphorylation** — Activates RAS/MAPK, PI3K/AKT, JAK/STAT, and other survival/proliferation pathways
3. **Impaired apoptosis** — Upregulates anti-apoptotic proteins (BCL-2, MCL-1)
4. **Altered adhesion** — Reduces interaction with bone marrow stromal cells, allowing leukemic blasts to escape the niche

**High-Yield:** BCR-ABL is the classic example of an oncogenic fusion protein. It is targetable by tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib), which revolutionized CML treatment.

**Clinical Pearl:** Imatinib (Gleevec) was the first targeted cancer drug approved by the FDA (2001) and dramatically improved CML survival from ~5 years to >20 years. This exemplifies precision medicine in oncology.

Answer

A. Overexpression of growth factor receptors on the cell surface

Answer

C. Loss of p53 function leading to impaired apoptosis

Answer

D. Inactivation of RB protein resulting in uncontrolled G1/S transition

Which of the following best describes the mechanism by which the BCR-ABL fusion protein (Philadelphia chromosome) drives chronic myeloid leukemia?

Explanation

BCR-ABL Fusion Protein and CML Pathogenesis

Philadelphia Chromosome: t(9;22) Translocation

Mechanism of Leukemogenesis

Why BCR-ABL Drives CML

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