NPM1c Posttranslational Glutamylation in Leukemogenesis
Abstract
Mutations in Nucleophosmin (NPM1) are found in up to 35% of adult patients with acute myeloid leukemia (AML). NPM1 is a ubiquitously expressed pentameric histone chaperone primarily localized to the nucleolus. The most common mutation in NPM1 seen in AML patients is in the C-terminus (NPM1c), which leads to cyto-plasmic mislocalization of the protein. However, the mechanisms by which NPM1ctransforms hematopoietic cells and confers leukemic self-renewal are poorly understood. An often-overlooked role of NPM1 is that of a histone chaperone. Histone chaperones function by preventing histone aggregation, facilitating their cytoplas-mic-nuclear transport, and deposition or removal from DNA. NPM1 binds core histones as well as linker his-tone (H1). Histones are a fundamental component of chromatin, which is the physiologic form of the eukaryotic genome. H1 dynamically associates with chromatin, promoting compaction into higher order structures and generally repressing gene expression. We showed that the enzyme TTLL4 post-translationally glutamylates NPM1 to alter its histone chaperone function. We hypothesize that aberrant glutamylation of the NPM1c mu-tant alters histone deposition at leukemogenic gene loci, thereby increasing expression and promotes leuke-mogenesis. In this project, we are testing how, when, and what TTLL4 and NPM1c do to promote leukemogen-esis and how TTLL4 may be an effective drug target.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219041
Entities
People
- David Shechter
- Kira Gritsman
Organizations
- Albert Einstein College of Medicine