In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myelodysplastic Syndrome

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Investigator: Kevin M. Shannon, MD

Location(s): United States

Description

Myelodysplastic Syndrome (MDS) is caused by genetic changes in immature bone marrow cells called hematopoietic stem cells (HSC) that produce mature blood cells throughout life. As a result of these genetic changes, a clone (or clones) of abnormal MDS HSC forms in the bone marrow and ultimately takes over. The genetic changes in MDS HSC also lead to the production of abnormal numbers of mature blood cells that often function poorly. As a result, many patients with MDS are susceptible to infections, require blood transfusions for anemia, and may have an increased risk of bleeding or developing blood clots. In some patients, MDS progresses to acute myeloid leukemia (AML}, which is characterized by additional genetic changes. Uncovering the genetic changes that cause MDS, understanding how these changes allow MDS HSC to replace normal HSC in the bone marrow, and determining why MDS patients have defects in blood cell production and sometimes develop AML are central questions that we must answer to develop better treatments for MDS.

In general, two major types of genetic alterations contribute to the formation and abnormal growth of MDS HSC. The first type involves mutations in specific genes encoding proteins that regulate blood cell growth and maturation. Applying new technologies for sequencing all of the genes in diseased bone marrow samples from MDS patients has led to immense new knowledge about gene mutations in this disease. These mutated genes make proteins that are involved in many fundamental cellular activities, which include processing RNA, controlling which genes are specifically expressed in HSC and mature blood cells, and regulating how MDS cells respond to growth factors and other cues. This new “roadmap” of genes that are mutated in MDS now allows researchers to probe how individual genes and proteins alter blood cell growth and to develop therapeutic strategies for attacking them.

The second major type of genetic alteration in MDS involves loss or gain of an entire chromosome-or very large deletions that remove part of a chromosome. Like most of the gene mutations found in MDS, these chromosomal changes are only present in MDS cells and are not found in the normal tissues of MDS patients. One of the most common chromosomal changes in MDS is loss of one copy of chromosome 7 (monosomy 7) or a deletion of the long arm of this chromosome, which is called del(7q). Since normal cells have two copies of chromosome 7, MDS cells with monosomy 7 lose one copy of all of the genes on chromosome 7 and those with a del(7q) delete most of the same genes. Cases of MDS with monosomy 7 or del(7q) are frequently aggressive (that is, patients have shorter survival and a higher risk of developing AML). Unfortunately, state-of-the-art DNA sequencing has not been very helpful in finding chromosome 7 genes that contribute to MDS. This is because mutations in chromosome 7 genes are uncommon in MDS cases with monosomy 7 and del(7q). That is, the bone marrows of these patients carries one copy of each gene that works normally. It is therefore likely that loss of one copy of many different 7q genes together contributes to MDS. Solving this problem is even harder than finding a “needle in a haystack” because the critical genes do not have mutations – it might be viewed as “finding hay in a haystack”. A segment of chromosome 7q called 7q22 is lost very commonly in the bone marrows of MDS patients.

The goals of our project are: (1) to identify genes located in 7q22 that play a role in MDS; and, (2) to create accurate mouse models of MDS with 7q22 deletions. We have used a technique called chromosome engineering to delete over 40 7q22 genes in mice. We will now use these novel strains to: (1) ask if these mice develop MDS; (2) characterize how loss of multiple 7q22 genes alters the growth of HSC; (3) determine how loss of these genes cooperates with other mutations found in MDS patients to cause this disease; and, (4) to test if loss of 7q22 genes works together with exposure to a class of alkylating chemotherapy drugs to induce MDS. Together, this work will both enhance our understanding of how chromosome 7 deletions contribute to MDS and will generate mouse models of MDS that can be used to test new treatments.