A 42-year-old woman with newly diagnosed acute myeloid leukaemia (AML) is started on chemotherapy with daunorubicin and cytarabine. After 5 days of therapy, peripheral blood shows a marked reduction in blast cells. A bone marrow biopsy reveals numerous apoptotic bodies within myeloid precursors. Which of the following best explains the mechanism of chemotherapy-induced apoptosis in these leukaemic cells?

Explanation

## Mechanism of Chemotherapy-Induced Apoptosis ### DNA Damage and p53 Activation Chemotherapy agents like daunorubicin and cytarabine cause direct DNA damage by intercalating into the DNA double helix and inhibiting topoisomerase II. This triggers the **intrinsic (mitochondrial) apoptotic pathway**. **Key Point:** DNA damage is sensed by ATM and ATR kinases, which phosphorylate and stabilize p53 — the "guardian of the genome." p53 then acts as a transcription factor to upregulate pro-apoptotic genes. ### Pro-Apoptotic Bcl-2 Family Members Stabilized p53 upregulates: - **BAX** and **BAK** — pro-apoptotic effectors that oligomerize in the outer mitochondrial membrane - **PUMA** and **NOXA** — BH3-only proteins that neutralize anti-apoptotic Bcl-2 and Bcl-xL This leads to mitochondrial outer membrane permeabilization (MOMP), release of cytochrome c, and formation of the apoptosome (cytochrome c + Apaf-1 + pro-caspase-9), activating the caspase cascade. ### Why This Is the Intrinsic Pathway The intrinsic pathway is **stress-induced** (DNA damage, hypoxia, growth factor withdrawal) and **p53-dependent**. It does not require external death receptor signals. **High-Yield:** Leukaemic blasts are highly proliferative and often have intact p53 function (unlike solid tumours). Chemotherapy exploits this by triggering p53-mediated apoptosis. **Clinical Pearl:** Leukaemias with p53 mutations (e.g., TP53 mutations in AML) are chemotherapy-resistant because they cannot mount a p53-dependent apoptotic response. ### Intrinsic vs. Extrinsic Pathways | Feature | Intrinsic (Mitochondrial) | Extrinsic (Death Receptor) | |---------|---------------------------|---------------------------| | **Trigger** | DNA damage, stress, growth factor withdrawal | Fas/FasL, TNF-R1, TRAIL-R | | **Key Protein** | p53, Bcl-2 family, mitochondria | Death receptors, DISC, caspase-8 | | **Checkpoint** | Bcl-2 vs. pro-apoptotic balance | FLIP inhibition | | **Caspase Initiator** | Caspase-9 (via apoptosome) | Caspase-8 (via DISC) | | **Cytochrome c Release** | Yes (MOMP) | No direct release | **Mnemonic:** **MOMP** = Mitochondrial Outer Membrane Permeabilization — the hallmark of intrinsic apoptosis.