NPM1c Posttranslational Glutamylation in Leukemogenesis
Abstract
As we focus on acute myeloid leukemia (AML), an aggressive form of blood cancer, this project addresses the Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Blood Cancers. About one-third of adult AML patients have an abnormal mutated form of the protein nucleophosmin (NPM1) in their leukemia cells, and some children with AML also have this mutation. It has been reported that AML cells with mutated NPM1 express high levels of HOX genes, which are very important for maintaining cells in the immature state. When HOX genes are expressed in the wrong cells or at the wrong time, this can lead to arrested maturation and transformation to a cancerous state. It has been shown that HOX gene expression is required for the ability of mutated NPM1 to transform blood cells to the malignant state. However, the mechanism by which mutated NPM1 causes inappropriate expression of HOX genes in blood cells is still poorly understood. Understanding this mechanism is critical to design specific treatments for this common class of AML. The NPM1 protein is a histone chaperone. Histones are like beads on a string, on which the DNA is wound and packaged. Changes in the way the DNA is packaged on specific histones can change how some genes are turned on or off. The job of a histone chaperone is to assist with the correct packaging of the DNA on histones. We hypothesize that the mutation seen in NPM1 in AML cells disturbs the histone chaperone function of NPM1, which leads to incorrect packaging of DNA, and therefore causes the HOX genes to turn on inappropriately. We propose that this is a critical mechanism by which the mutant NPM1 transforms cells and causes them to divide uncontrollably. One way that the histone chaperone activity of NPM-related proteins can be regulated is by addition of glutamic acid to the protein by the enzyme TTLL4; this process is known as glutamylation. We hypothesize that inactivation of TTLL4 will prevent the abnormal association of mutated NPM1 with histones and will therefore allow blood cells to mature normally. To test this hypothesis, we will (1) test how glutamylation of the mutant NPM1 affects its binding to histones, (2) examine how glutamylation of NPM1 affects the ability of histones to correctly package DNA in the region of the HOX genes, and (3) determine whether inactivation of TTLL4 can interfere with the ability of mutant NPM1 to transform normal blood cells into leukemic cells. As a result of this work, we anticipate that the understanding of the mechanism of transformation by mutant NPM1 in AML will be greatly improved. Furthermore, this project will test TTLL4 as a novel therapeutic target for treating patients with NPM1-mutated AML, focused on inhibiting the glutamylation of mutated NPM1. In the future, we will work to design specific strategies to inhibit both TTLL4 and glutamylation of NPM1. Because NPM1 has also been found in patients at the time of relapse after initial chemotherapy, it is particularly important to learn how to specifically eliminate cells expressing mutated NPM1. Once specific treatments for AML with mutated NPM1 are available, they could either be added to standard chemotherapy, or they could also be given after initial treatment to patients with residual AML cells with mutated NPM1 to prevent relapse. We anticipate that specific inhibition of the inappropriate chaperone activity of mutated NPM1 will improve the chances of long-term survival for this sizeable group of AML patients. This proposal will have high relevance for military Service Members, Veterans, and their families, because an elevated risk of AML has been reported in several military populations, such as Korean War Veterans, and children of Vietnam War Veterans. Furthermore, the risk of death for military Service Members with AML is more than twice that of civilians with AML. Because NPM1 is mutated in over one-third of AML patients, identifying new therapeutic targets specific
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110863
Entities
People
- David Shechter
Organizations
- Albert Einstein College of Medicine
- United States Army