A 52-year-old man with newly diagnosed acute myeloid leukemia (AML) is being considered for induction chemotherapy. The treatment strategy aims to trigger apoptosis in leukemic blasts via the intrinsic (mitochondrial) pathway. Which of the following drugs is the drug of choice for inducing apoptosis through BCL-2 inhibition in AML?

Explanation

## BCL-2 Inhibitors in AML **Key Point:** Venetoclax is a selective BCL-2 inhibitor that directly antagonizes the anti-apoptotic BCL-2 protein, allowing pro-apoptotic proteins (BAX, BAK) to oligomerize on the mitochondrial outer membrane and trigger the intrinsic apoptotic pathway. **High-Yield:** Venetoclax + hypomethylating agents (azacitidine or decitabine) is now the standard of care for elderly or unfit patients with newly diagnosed AML who are ineligible for intensive chemotherapy. It has dramatically improved outcomes in this population. **Clinical Pearl:** The intrinsic apoptotic pathway is regulated by the BCL-2 family of proteins: - **Anti-apoptotic:** BCL-2, BCL-XL, MCL-1 - **Pro-apoptotic:** BAX, BAK, BIM, PUMA, NOXA Venetoclax works by sequestering anti-apoptotic BCL-2, freeing pro-apoptotic proteins to initiate mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release. ## Mechanism of Apoptosis Induction ```mermaid flowchart TD A[Venetoclax binds BCL-2]:::action --> B[BCL-2 inactivated]:::outcome B --> C[BAX/BAK freed]:::action C --> D[MOMP occurs]:::outcome D --> E[Cytochrome c released]:::outcome E --> F[Apoptosome formation]:::action F --> G[Caspase-9 activation]:::action G --> H[Caspase-3/7 activation]:::action H --> I[Apoptosis]:::outcome ``` **Mnemonic:** **VENICE** = **V**enetoclax **E**nhances **N**ecrosis via **I**ntrinsic **C**ytochrome **E**vents [cite:Robbins 10e Ch 2]