Questions and answers about clonal hematopoiesis.
What is hematopoiesis?
Hematopoiesis refers to the body’s biological process of making blood. Our bone marrow contains blood-forming cells termed “hematopoietic stem cells.” These stem cells produce all the blood cells in our body.
What is clonal hematopoiesis (CH)?
Our blood-forming cells are in a constant state of division to make mature blood cells. As we age, genetic mistakes can happen during this process causing a mutation. Sometimes, blood cells carrying these mutations out-compete normal blood cells. Blood cells carrying these mutations are a “clone” having been derived from the same ancestral mutated blood cell. Thus, the phenomenon is termed “clonal hematopoiesis” – sometimes abbreviated “CH”. Other names used are “clonal hematopoiesis of indeterminate potential” (CHIP) or age-related clonal hematopoiesis (ARCH).
What are the risks associated with CH?
A number of studies have shown that CH increases the likelihood of eventual blood cancer (e.g. leukemia, lymphoma, multiple myeloma) and cardiovascular disease. Based on current knowledge, the absolute risk of blood cancer for any one person is low, but has been estimated at 0.5-1% per year by some reports. The risk of cardiovascular disease is approximately 2-fold. Because CH is associated with inflammation, there may be other diseases that might be affected by CH and scientists are working hard to discover them.
What can I do about CH?
CH has been associated with smoking and is linked to increased risk of cardiovascular diseases in addition to blood cancers. Smoking cessation is thus important. If you have CH and would like to speak with a physician about your mutation and possible risk management, please call Dr. Pinkal Desai at 646-962-2700.
I have CH. Did I get it from my parents? Will my children get it?
Based on current knowledge, specific CH mutations are not inherited from your parents and cannot be passed on to your children. Some inherited gene variations may increase the risk of getting CH, but this research is still ongoing.
What environmental or external risk factors can increase the chance of progression to blood cancers?
Sometimes, exposure to radiation or chemotherapy will increase risk of blood cancers if you happen to have CH. Smoking has been associated with particular types of CH mutations. We are actively doing research in this field to monitor and identify risk factors that can impact the progression from CH to blood cancer.
How common is CH in Individuals?
CH is common and can be found in 25-30% of individuals over 60 years of age and in 10% of individuals between 50-60 years of age. However, not all presentations of CH mutations are high-risk for developing or impacting diseases in the future. Thus, proper mutation-specific monitoring is important.
How can CH be detected?
CH is detected using a technology called “next generation sequencing,” in which the DNA sequence is determined for individual DNA molecules in your blood. Our Institute’s Molecular Aging Initiative has developed the PreCISE-1 test to help predict disease risk based on specific CH mutation patterns (PreCISE-1 is currently approved for research purposes only). To request testing for CH in a clinical or research setting, please e-mail Dr. Duane Hassane at firstname.lastname@example.org.
How sensitive must a test be to detect CH?
Research is still ongoing to develop these guidelines. Mutations present in 1 in 25 blood cells have been proposed as comprising CH (allelic fraction >2%). However, we have shown that mutations in the isocitrate dehydrogenase genes (IDH1, IDH2), for example, can increase acute myeloid leukemia risk when present just above 1 in 50 cells (allelic fraction >1%). Thus, risk likely depends on what gene is mutated, how it is mutated, and percentage of mutated cells.
What mutations are responsible for CH?
The most common mutations observed are in the genes DNMT3A, TET2, and ASXL1. More rarely, mutations have been found in genes such as spliceosome genes, TP53, CBL, JAK2, IDH1, and IDH2.
Aren’t CH mutations found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)?
Yes, these are the same mutations that are found in MDS and AML. Medical professionals believe that these mutations are present many years before the onset of MDS and AML, but the absolute risk for progression of these mutations to MDS or AML is low. Additional mutations may be required for the development of blood cancer. Our program is focused on identifying these features that distinguish people at higher risk for progression compared to others. Physicians and scientists at Weill Cornell Medicine, including Dr. Pinkal Desai and Dr. Duane Hassane, are leading the charge in this area of research and were among the first to determine what CH mutations pose the greatest risk of acute myeloid leukemia.
WHO CAN I CONTACT?
For clinical inquiries please contact Pinkal Desai, M.D. (below left) in the WCM Hematology and Oncology Department, via email: email@example.com. For scientific and research questions please contact Duane C. Hassane, Ph.D. (below right) in the WCM Leukemia Department, via email: firstname.lastname@example.org.
Desai P, Mencia-Trinchant N, Savenkov O, Simon MS, Cheang G, Lee S, Samuel M, Ritchie EK, Guzman ML, Ballman KV et al. 2018. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nature medicine 24: 1015-1023.
Kaner J, Desai P, Mencia-Trinchant N, Guzman ML, Roboz GJ, Hassane DC. 2019. Clonal Hematopoiesis and Premalignant Diseases. Cold Spring Harb Perspect Med.
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A et al. 2014. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371: 2488-2498.
Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D et al. 2017. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377: 111-121.
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Cook EK, Izukawa T, Young S, Rosen G, Jamali M, Zhang L, Johnson D, Bain E, Hilland J, Ferrone CK et al. 2019. Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis. Blood Adv 3: 2482-2486.
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. 2015. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126: 9-16.
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