Diseases
Why Do Mutations in DNA Matter?
As we age, mutations in DNA gradually accumulate in cells throughout our body. Most of these mutations have no effect on the biology of the cell in which they arise, but this is not always the case. For example, if you change a single letter in a word in a sentence, the change usually does not alter the meaning of the sentence. However, occasionally that single letter change can completely alter a word and thus the meaning of the entire sentence. If a mutation in the DNA alters the biology of a cell and renders that cell more “fit” than surrounding cells without that mutation, then the mutant cell may outcompete its neighbors and be selected for over time. These selected cells are referred to as “clonal” since they all carry the same mutation. This process can continue with the accumulation of additional mutations, altering the biology of the mutant cells so much that they begin to grow uncontrollably, ultimately giving rise to what we call cancer.
What is Clonal Hematopoiesis?
When the process described above occurs in the hematopoietic system (the blood-producing system), it is called "Clonal Hematopoiesis.” This term simply means that a clonal population of cells carrying an alteration in the DNA is present in the blood. Even though we have about 20,000 genes (sections of the DNA that encode for proteins), only about 100 genes are usually mutated in blood cells, likely reflecting the particular importance of this subset of genes to the biology of blood cell production, growth, and survival. The term clonal hematopoiesis of indeterminate potential (“CHIP”) describes the case when an individual has clonal hematopoiesis without any evidence of blood disorder (such as low blood counts or a blood cancer).
Broadly speaking, clonal hematopoiesis can have two consequences. First, individuals with clonal hematopoiesis are more likely to develop blood cancers including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) via the acquisition of additional mutations. In this sense, clonal hematopoiesis can be considered a “pre-malignant” state, akin to how people think about a polyp in the case of colon cancer or a mole in the case of melanoma. Second, we now know that individuals with clonal hematopoiesis are at higher risk for developing various “non-hematopoietic” diseases, such as cardiovascular disease or chronic obstructive pulmonary disease (COPD), independent of the risk of developing MDS or AML. This seems to occur because the clonal hematopoietic mutations not only increase the likelihood of acquiring additional mutations and transforming to cancer, but also alter the inflammatory state of the immune cells carrying these mutations.
Our lab is interested in understanding both consequences of clonal hematopoiesis:
How do these mutations lead to MDS and AML and when present in these cancers how can we better treat them?
How do these mutations alter inflammatory states and contribute to “non-hematopoietic” disease states, in particular COPD?
What are MDS and AML?
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are cancers of a class of blood cells called myeloid cells. Both MDS and AML are caused by abnormal myeloid cell biology, usually as a result of mutations present in the cells. In both MDS and AML there is aberrant production of cancer cells called “blasts” and insufficient production of the normal blood cells required to carry oxygen (red blood cells), fight infection (white blood cells), and prevent bleeding (platelets). MDS and AML are distinguished based on the number of blasts presents, with the latter having more blasts and often a more advanced disease. Both MDS and AML are potentially lethal diseases due to risks associated with a high number of blasts (causing blood flow to slow due to high viscosity and secreting factors that drive tissue inflammation and promote clotting) and insufficient production of normal cells (bleeding, infection, ischemia). New treatments are necessary for these diseases, particularly the forms that are considered “high risk” based on genetic and clinical characteristics.