A 70-year-old man with AML shows t(15;17) on cytogenetics and responds dramatically to all-trans retinoic acid (ATRA). Why does ATRA work specifically in this subtype?

• A ATRA activates caspase-3 directly in promyelocytes, bypassing the PML-RARA block
• B ATRA induces hypermethylation of the PML-RARA promoter, silencing the fusion oncogene
• C ATRA competitively inhibits the kinase domain of the PML protein
• D ATRA binds the RARA portion of the PML-RARA fusion, relieving transcriptional repression and restoring myeloid differentiation ✓

Explanation

In APML, the PML-RARA fusion protein recruits histone deacetylases (HDAC), blocking myeloid differentiation. Pharmacological doses of ATRA bind the RARA portion of the fusion, inducing a conformational change that releases corepressors, restores transcriptional activation of differentiation genes, and promotes terminal differentiation of leukemic promyelocytes. This targeted differentiation therapy has transformed APML from the most fatal to the most curable AML subtype.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.