TY - JOUR
T1 - Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors
AU - Dulmovits, Brian M.
AU - Appiah-Kubi, Abena O.
AU - Papoin, Julien
AU - Hale, John
AU - He, Mingzhu
AU - Al-Abed, Yousef
AU - Didier, Sebastien
AU - Gould, Michael
AU - Husain-Krautter, Sehba
AU - Singh, Sharon A.
AU - Chan, Kyle W.H.
AU - Vlachos, Adrianna
AU - Allen, Steven L.
AU - Taylor, Naomi
AU - Marambaud, Philippe
AU - An, Xiuli
AU - Gallagher, Patrick G.
AU - Mohandas, Narla
AU - Lipton, Jeffrey M.
AU - Liu, Johnson M.
AU - Blanc, Lionel
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016/3/17
Y1 - 2016/3/17
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2015-09-667923
DO - 10.1182/blood-2015-09-667923
M3 - Article
C2 - 26679864
AN - SCOPUS:84961833440
SN - 0006-4971
VL - 127
SP - 1481
EP - 1492
JO - Blood
JF - Blood
IS - 11
ER -