Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors

Brian M. Dulmovits, Abena O. Appiah-Kubi, Julien Papoin, John Hale, Mingzhu He, Yousef Al-Abed, Sebastien Didier, Michael Gould, Sehba Husain-Krautter, Sharon A. Singh, Kyle W.H. Chan, Adrianna Vlachos, Steven L. Allen, Naomi Taylor, Philippe Marambaud, Xiuli An, Patrick G. Gallagher, Narla Mohandas, Jeffrey M. Lipton, Johnson M. LiuLionel Blanc

Research output: Contribution to journalArticlepeer-review

Abstract

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably,the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levelsin their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies. (Blood.

Original languageEnglish (US)
Pages (from-to)1481-1492
Number of pages12
JournalBlood
Volume127
Issue number11
DOIs
StatePublished - Mar 17 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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