Figure 2.

Pathological condensation of AML oncoproteins. (A) Endogenous NUP98 localizes to the nuclear membrane whereas oncogenic NUP98 fusion proteins form nuclear condensates that are required for the induction of leukemic transcriptional programs and transformation. (B) Endogenous PML forms nuclear bodies through oligomerization. Nuclear PML bodies have tumor-suppressive functions by regulating chromatin modifications, DNA damage repair, and protein degradation. In APL, the PML::RARA fusion protein disrupts the formation of physiological PML bodies and impedes their tumor-suppressive functions. PML::RARA is neddylated at the RARA moiety leading to enhanced chromatin binding and inhibition of PML:PML interactions. (C) NPM1 is mainly localized to the nucleolus, where it is involved in ribosome biogenesis. Insertion and frameshift mutations (fs) lead to insertion of a NES, causing the relocation of NPM1c to the cytoplasm and to nuclear speckles. Within nuclear condensates NPM1c binds to chromatin that is prebound by XPO1, removes repressive HDACs, and further recruits RNA-Pol II to induce leukemic gene expression. AML = acute myeloid leukemia; HDAC = histone deacetylase; NES = nuclear export signal; PML = promyelocytic leukemia protein.