Human and Mouse Models of DDX41-Mutated Myelodysplastic Syndrome
Abstract
Most inherited gene mutations that cause bone marrow failure (BMF) are associated with health conditions from birth or they cause blood and bone marrow disease in adolescence. In contrast, inherited mutations in the gene DDX41 are associated with high likelihood of developing myelodysplastic syndrome (MDS) but not until the sixth decade of life or later. Patients with inherited DDX41 mutations account for 3%-5% of all adult MDS patients. However, the role of these initially silent mutations in causing MDS is poorly understood. We seek to create disease models to help elucidate the role of DDX41 mutations in MDS and to identify new ways to treat these patients. This proposal addresses both of the Idea Development Award Focus Areas in that it seeks to understand the cause and progression of BMF diseases and to find effective treatments and cures. Stem cells residing in the bone marrow are responsible for the constant production of blood cells. Defects in these stem cells lead to bone marrow failure diseases like MDS, which occurs when bone marrow stem cells fail to produce normal blood cells of sufficient abundance and quality to maintain health. In most cases, MDS is a disease of the elderly, arising in patients in their seventh decade of life or later. A likely reason for the advanced age at disease onset is that multiple gene mutations affecting the function of stem cells are required for the disease to arise. In patients with a DDX41 mutation in their DNA since birth, MDS can occur slightly earlier than the general group of MDS patients but much later than other inherited bone marrow failure disorders. This suggests that DDX41 mutations on their own do not cause MDS, and additional mutations are required. Indeed, in most patients, at least one other mutation associated with blood disorders and cancers is present in the bone marrow. In the proposed experiments, we will generate genetically-modified mice and human stem cells to serve as models of MDS caused by DDX41 mutations. We will then use those models to determine how the mutations in DDX41 and other genes cooperate to cause MDS. Once we know how the mutations in DDX41 and other genes alter the bone marrow stem cells, we can identify potential targets for the design of drugs that would eliminate these MDS stem cells. One interesting facet of MDS caused by DDX41 mutations is that more than half of the patients acquire a second mutation in DDX41 in their bone marrow cells. Since there are two copies of DDX41 in DNA, this means that both copies of DDX41 are mutated in these patients’ cells. To model this facet of the disease, we have created genetic mouse strains that contain the same mutations in DDX41 as patients have in their DNA. We used them to determine that mice containing both of the DDX41 mutations cannot survive due to total failure of the bone marrow to produce blood cells. This indicated that at least one copy of DDX41 is required for bone marrow stem cells to produce blood cells. We found that the failure of the stem cells with two DDX41 mutations to produce blood was likely caused by a defect in the cells’ ability to make new proteins, which they must do in order to produce new cells. While these findings solved one part of the mystery of why cells with two DDX41 mutations cannot make blood normally, it left several questions unanswered. The first of these is why patients with only one DDX41 mutation get MDS. The second is why bone marrow stem cells that acquire the second DDX41 mutation don’t just die but instead accumulate in the bone marrow. To answer these questions, we will expand the mouse models that were described in our paper to include mutations in other genes that are common in DDX41 patient bone marrow cells, and then we will also generate human cell models that accurately replicate the mutations present in patients. While there are many other genes where mutations have been observed in the DDX41 patients’ bone marrow
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210805
Entities
People
- Timothy Chlon
Organizations
- United States Army