Thalidomide analogs exhibit differential effects in driving selection of TP53-mutant HSPC clones. Thalidomide and its analogs function by increasing the affinity of the CRL4CRBN E3 ubiquitin ligase for specific protein substrates, including key transcription factors IKZF1, ZFP91, and casein kinase 1α (CK1α), which are critical for HSPC survival. Lenalidomide leads to a specific positive selection of TP53-mutant clones by inducing CK1α degradation and p53-dependent apoptosis in normal HSPCs. Another thalidomide analog, pomalidomide, induces degradation of IKZF1 and ZFP91 but does not induce CK1α degradation or apoptosis, and thus HSPCs do not experience the same selection pressure. Subsequent outgrowth of TP53-mutant HSPC clones in the context of lenalidomide treatment increases the risk of t-MN development. However, it is unknown if pomalidomide therapy is a risk factor for t-MN. Professional illustration by Somersault18:24.