Investigating the cooperating factors of NPM1c on chromatin in AML

Nucleophosmin 1 (NPM1) mutations are the most common genetic lesion in acute myeloid leukemia (AML), found in one-third of cases and leading to the cytoplasmic mislocalization of the protein (NPM1c). Until now, the focus on NPM1c in leukemia was predominantly centred on its cytoplasmic activities. However, we recently showed a pivotal role for NPM1c within the very core of leukemia cells - the nucleus - where it binds to chromatin at important self-renewal-associated gene loci, such as HOXA/B and MEIS1, and directly regulates the oncogenic transcription. Now the critical question is which other nuclear factors cooperate with NPM1c to drive leukemic transformation. Using proximity labelling and mass spectrometry, we identified nuclear pore complex (NPC) proteins as potential cooperating factors of NPM1c. To investigate their functional relevance, we are employing chromatin binding studies, CRISPR-Cas9 editing and targeted protein degradation techniques to determine how nucleoporins cooperate with NPM1c in leukemia development. This study aims to expand our understanding of disease development and thereby identify molecular targets for potential new epigenetic therapies.

Publication History

Article published online:
09 May 2025