Pomalidomide affects lineage commitment in a NSG mouse model. (A) NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) mice received fetal CD34⁺ cells IV for engrafting with human hematopoiesis. (B) NSG mice exhibiting human hematopoiesis were injected IV with DMSO (0.1%, 100 µL) or POM (300 µg/kg) every 2 days. Three weeks later, bone marrow cells were subjected to flow cytometry for the detection of human progenitor cells, gated with human CD45⁺CD34⁺, and analyzed using antihuman CD45RA, CD38, CD10. Murine erythroid Ter119⁺ and Ly5⁺ cells and nucleated cells were excluded. (C) The partial bone marrow cells were sorted using human CD34⁺ MACS beads. The sorted cells were subsequently used for colony-formation assays. After 14 days, colony numbers were counted. (D) IMiD compounds directly bind to CRBN in human CD34⁺ cells, which leads to IKZF1 ubiquitination and promotes protein degradation. The loss of IKZF1 decreases PU.1 expression in human CD34⁺ cells and leads to a shift to myeloid lineage commitment with inhibition of myeloid maturation. The inhibition of myeloid maturation might lead to neutropenia and an increased risk for secondary malignancies. *P ≤ .05.