Reducing the risk of blood cancer with age by weeding out leukemia-causing stem cells in the bone marrow
Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the lifetime generation of all the cells of the blood system. Blood cancers such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) arise from genetic mutations that alter how HSCs divide and produce mature blood cells.
New advances in genome sequencing reveal the spectrum of mutations present in AML and MDS patients and highlight how these diseases develop. Most of these cancers have relatively few mutations, which are acquired in a step-wise procession over a long period of time. The first mutation acquired (the “founding” or “initiating” mutation) generally acts to stop the HSC from turning into a mature blood cell, which leads the mutant cell to reproduce itself and take over in the bone marrow. This process is called clonal expansion. Many founding mutations affect genes involved in controlling the DNA modifications, which are called epigenetic marks. The two most common mutations are the enzymes DNMT3A and TET2, which regulate the epigenetic mark of DNA methylation. In the next step to cancer, a mutant cell acquires a second genetic mutation that increases proliferation, but the rate of this progression is highly variable, and acquiring these cancer-causing mutations in the correct order can take decades.
We know this because mutations in DNMT3A and TET2 are commonly found in the blood of healthy elderly people who have no signs of disease. This is known as clonal hematopoiesis of indeterminate potential (CHIP). An individual with CHIP has a 100-fold increased lifetime risk of developing a blood cancer; however, any technique to slow growth of these mutant cells during the CHIP phase will reduce that lifetime blood cancer risk and represent a breakthrough in cancer prevention.
Despite advances in genomics, cure rates for AML and MDS patients have not substantially improved in the last 40 years. Rather than focus on new treatments for the mature disease, which may only extend a patient’s lifespan a few months, we propose to eliminate the HSCs carrying cancer-causing mutations before they have a chance to acquire secondary mutations. The long timescale required for the evolution of these diseases presents a unique opportunity for cancer prevention. Using sensitive deep-sequencing techniques, we can accurately identify elderly individuals who carry blood cells with DNMT3A or TET2 mutations. The goal of this project is to develop a way to weed-out mutant HSCs, while sparing healthy cells, by targeting pathways only the mutant cells require for their propagation.