A patient with sickle cell disease starts hydroxyurea therapy. After 3 months, HbF rises from 4% to 22%. The mechanism by which hydroxyurea increases HbF involves inhibition of which enzyme, and which transcription factor does this ultimately reactivate?

• A Thymidylate synthase; KLF1
• B Ribonucleotide reductase; BCL11A ✓
• C Ribonucleotide reductase; gamma-globin gene promoter binding of KLF1
• D DNA polymerase delta; NF-E2

Explanation

Hydroxyurea inhibits ribonucleotide reductase (RNR), causing replication stress that activates stress erythropoiesis with accelerated production of early erythroid precursors (stress BFU-E). These stress erythroid progenitors express lower levels of BCL11A, the master repressor of gamma-globin transcription, and higher levels of gamma-globin. BCL11A normally silences the fetal gamma-globin genes in adult erythropoiesis; its downregulation by replication stress allows gamma-globin reactivation and HbF synthesis. KLF1 activates BCL11A expression and is upstream of this process.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.