Mechanisms of oncogenic transcription in NPM1-mutant myeloid leukemia
Reina Takeda
MD, PhDDana-Farber Cancer Institute
Project Term: July 1, 2024 - June 30, 2026
NPM1-mutated leukemia is the most common AML in adult and characterized by upregulations of HOXA/B genes and MEIS1. Given the importance of oncogenic transcriptional program, I will determine regulatory molecules that cooperate with mutant NPM1 on chromatin by combining CRISPR/Cas9 screening approach in an innovative model system of endogenous transcription reporters with proteomics approach. This will facilitate identification of novel therapeutic targets specific for NPM1-mutated AML.
Patients with Acute myeloid leukemia (AML) continue to have an inferior prognosis. The standard therapeutic regimens for AML consist of combination chemotherapy and stem cell transplantation. Some patients cannot receive these intensive treatment strategies because of their advanced age, their other underlying health problems that put them at risk for treatment-related toxicity, or lack of stem cell transplant donors, and this also poses a clinical challenge. Recent advances in understanding the genetic drivers of AML have revealed that the disease profile varies greatly depending on the specific mutation. Therefore, the development of targeted therapies for driver mutations is urgently needed to improve the outcome of AML patients.
Mutations in the nuclear chaperone nucleophosmin (NPM1) gene are one of the most common mutations in AMLs in adults, accounting for one-third of cases. Despite being one of the most frequently detected leukemia subtypes, specific targeted therapies for NPM1-mutant AML are lacking. Further, the manner in which NPM1 mutations drive normal blood cells to transform into AML is not fully understood. Therefore, it is critical to understand the molecular mechanisms underlying this transformation caused by NPM1 mutations in order to develop novel targeted therapeutics and improve patient outcomes.
We recently reported that mutant NPM1 proteins (NPM1c) produced by NPM1 mutations bind to chromatin. Chromatin is an important complex of DNA and proteins which determines which genes are turned on or off. This chromatin-binding ability of NPM1 thus may be involved in regulating the expression of oncogenes that cause or sustain cancer cells. However, the detailed regulatory mechanisms of this oncogenic gene transcription driven by NPM1c remain largely unknown. In this proposal, I established an innovative reporter system using gene editing technology to visualize oncogenic transcription in human NPM1-mutated AML cells. Using the transcriptional reporter cells together with a proteomic approach, I propose to elucidate how NPM1c orchestrates the oncogenic transcriptional regulatory system and maintains leukemia cell growth. This project will provide insights into the regulation of oncogenic transcription and uncover potential avenues for the rational development of novel therapeutic strategies that can specifically target NPM1-mutated AML and perhaps other leukemias as well.