A 28-year-old woman presents with a 2-week history of gum bleeding, epistaxis, and petechiae. Laboratory studies show pancytopenia, prolonged PT/PTT, fibrinogen 80 mg/dL, and D-dimer >10 μg/mL. Bone marrow examination reveals the abnormal cells marked **A** in the diagram — hypergranular promyelocytes with bundles of Auer rods (faggot cells). Which of the following best explains the molecular pathogenesis of this disease?

Explanation

## Why PML-RARA dominant-negative inhibition is right The structure marked **A** — hypergranular promyelocytes with faggot cells (bundles of Auer rods) — is pathognomonic for acute promyelocytic leukemia (APL/AML M3), which is defined by the balanced reciprocal translocation t(15;17)(q22;q12) generating the PML-RARA fusion gene. The PML-RARA fusion protein acts as a dominant-negative inhibitor of normal retinoic acid receptor α (RARA), recruiting nuclear corepressors and histone deacetylases that block terminal myeloid differentiation at the promyelocyte stage, even at physiologic retinoic acid concentrations. This molecular mechanism is the foundation of APL pathogenesis and explains why pharmacologic doses of all-trans retinoic acid (ATRA) can dissociate the corepressor complex and induce terminal differentiation — one of the most successful targeted therapies in oncology (Harrison 21e Ch 105). ## Why each distractor is wrong - **NPM1 mutation impairs nucleolar protein export**: NPM1 mutations are the most common genetic abnormality in cytogenetically normal AML (CN-AML) and define a distinct AML subtype with cup-like nuclear indentations (structure **B** in the diagram), not the hypergranular promyelocytes with Auer rods seen in APL. NPM1 mutations do not cause APL. - **PLZF-RARA translocation creates ATRA-resistant fusion**: While t(11;17) PLZF-RARA is indeed a rare ATRA-resistant variant of APL, it accounts for <1% of APL cases and is not the defining molecular abnormality of the classic hypergranular APL shown in structure **A**. The classic APL is defined by t(15;17) PML-RARA, not PLZF-RARA. - **Biallelic CEBPA mutations disrupt granulocytic maturation**: CEBPA mutations define a distinct AML subtype (AML with biallelic CEBPA mutation) characterized by FAB M1/M2 morphology with maturation, not the pathognomonic faggot cells of APL. CEBPA mutations do not cause APL. **High-Yield:** APL = t(15;17) PML-RARA dominant-negative inhibitor of RARA → ATRA dissociates corepressors → differentiation; faggot cells (Auer rod bundles) are pathognomonic; START ATRA immediately before genetic confirmation because of life-threatening DIC. [cite: Harrison 21e Ch 105; Robbins 10e Ch 13]