Mutations in SETBP1 cause protein overexpression and lead to loss of tumor suppressor function and altered myeloid transcription factor expression. CNL-associated mutations in SETBP1 occur in the β-TrCP1 degron motif. β-TrCP1 binding leads to formation of an E3 ligase complex to degrade SETBP1. Mutations in the degron motif therefore lead to SETBP1 overexpression, which can cause stabilization of its binding partner SET, and together they can inhibit the tumor suppressor PP2A. In addition, SETBP1 binds to the RUNX1 promoter and when overexpressed, it recruits the nucleosome remodeling deacetylase (NuRD) complex to the RUNX1 promoter, inhibiting transcription of this important myeloid regulator. AT-hook, DNA-binding motif that prefers AT-rich sequences; SKI, V-Ski avian sarcoma viral oncogene homolog.