Red blood cells from MM patients treated with pomalidomide show increased levels of γ-globin and proposed model. Whole-blood samples were obtained from MM patients treated with pomalidomide for varying doses and durations. (A) Coomassie gel staining of normal hematologic control vs MM patients treated with pomalidomide. (B) Expression levels of α- and γ-globin chains in RBCs derived from 3 MM patients treated with pomalidomide for different periods of time. The asterisk next to the time points for patient #2 denotes that the patient interrupted treatment during the time course of the study. (C) Proposed model: In the absence of pomalidomide, adult hematopoietic progenitors differentiate to erythroid progenitors that express BCL11A, SOX6, KLF1, LSD1, GATA1, GATA2, CoREST, HDAC1, and Mi2β. Erythroid progenitors downregulate GATA2 as they progress to terminal erythroblasts. High expression of these factors in erythroid progenitors (bold text) and erythroblasts lead to RBCs containing predominantly HbA with low levels of HbF (shaded text). In the presence of pomalidomide, there is an immediate loss of IKZF1 via proteasomal degradation in HSPCs and erythroid progenitors. However, this post-translational regulation of IKZF1 is independent of the transcriptional/post-transcriptional reprogramming event that we observe in erythroid progenitors, whereby the expression levels of key γ-globin repressors are reduced. This regulation is highly selective because HDAC1, CoREST, GATA2, and mi2β exhibit normal expression. As reprogrammed progenitors mature into erythroblasts, GATA2 is lost, the levels of BCL11A and SOX6 remain decreased, and KLF1, LSD1, and GATA1 expression normalizes. Ultimately, macrocytic (indicated by larger size) RBCs containing high amounts of HbF are produced.