A unified model: chromatin-bound multi-component onco-condensates.

In cells, highly coordinated multivalent interactions give rise to discrete functional assemblies-commonly referred to as biomolecular condensates-that compartmentalize the molecular components required for specific biological reactions. These condensates are increasingly recognized as organizational entities with central roles in normal cellular regulation and in the pathogenesis of human cancers. In a recent issue of Cell, Datar and colleagues investigated the condensation of NPM1c, a common gene mutation in acute myeloid leukemias (AMLs). They demonstrated the necessity and sufficiency of NPM1c in forming nuclear condensates termed coordinating bodies (C-bodies), which show co-partitioning of a suite of transcriptional coactivators such as NUP98, KMT2A/MLL1, Menin and XPO1/CRM1. While C-bodies are necessary for driving NPM1c-mutant AMLs, blockade of the co-partitioned component within C-bodies, such as the XPO1/CRM1 or Menin interaction by inhibitors, significantly alters the condensate composition and functionality. Likewise, a systematic deletion study of various regions within NPM1c pointed to a role for the coordinated multivalent interaction in establishing the functional condensates, as previously reported in studies of the Wilms tumor-causing ENL mutants and AML-causing NUP98 onco-fusions. Co-mixing of C-bodies and condensates formed by the onco-fusion of NUP98 or KMT2A/MLL1 in cells suggested them to be biophysically indistinguishable, indicative of a shared pathogenic mechanism. Altogether, recent studies of multiple genetic drivers in human cancers have revealed a type of chromatin-bound multi-component onco-condensates, which shall motivate the development of onco-condensate disruptors that could potentially be used as the broad treatments for cancer.

Duke Scholars

Author G. Greg Wang Pharmacology & Cancer Biology