Weekly SCD Practice Update

Hydroxyurea Decreases BCL11A and ZBTB7A/LRF Expression in Erythroid Cells, Including Human Progenitors, Providing Support in Raising Fetal Hemoglobin Levels in Sickle Cell Disease

Key Findings

  • Purpose To investigate whether hydroxyurea (HU) modulates expression of transcriptional repressors that silence fetal γ-globin genes, thereby clarifying the molecular mechanism of HbF induction.
  • Population Experiments were conducted in murine erythroleukemia (MEL) cells, human K562 erythroleukemia cells, and human CD34+ hematopoietic stem cell derived erythroid progenitors (in vitro).
  • Headline Result HU reduced protein and mRNA levels of BCL11A and ZBTB7A/LRF in erythroid cells. In primary human erythroid progenitors, HU added early in differentiation increased HbF from a baseline of ~8% to as high as ~23%. However, higher HU concentrations impaired maturation and proliferation, underscoring the therapeutic balance between efficacy and cytotoxicity.
  • Why It Matters This study provides direct mechanistic evidence that HU helps ‘lift the brakes’ on γ-globin expression by lowering transcriptional repressors. These insights strengthen the biologic rationale for HU therapy in SCD and may guide dosing strategies and inform next-generation HbF-inducing approaches.
  • Evidence Gaps Findings are restricted to controlled laboratory conditions (in vitro). Whether these molecular effects translate consistently in patients and across diverse dosing regimens requires confirmation in in vivo and clinical settings.
Source: Journal of Sickle Cell Disease – Hydroxyurea reduces the levels of the fetal globin gene repressors ZBTB7A/LRF and BCL11A in erythroid cells in vitro.

Regulatory & Guideline Watch

Hydroxyurea (HU) remains the only FDA-approved pharmacologic agent specifically indicated to reduce complications in sickle cell disease by inducing HbF. While guidelines already recommend HU for most eligible patients, mechanistic studies such as this reinforce its foundational role and may inform the development of next-generation HbF-modulating therapies.