How the Genetics of Blood Stem Cells Can Lead to Cancer and Heart DiseaseNews
The Context: All of our blood cells — including our immune cells — come from a special type of stem cells known as ‘hematopoietic stem cells’ or ‘HSCs.’ As we age, HSCs can accumulate genetic mutations, which can increase our chances of developing cancer and heart disease. But why does this only happen in some people?
The Study: In two studies of thousands of people published in Nature, researchers have identified inherited genetic factors that increase individual risk for accumulating harmful mutations in HSCs, in turn leading to blood disorders known as myeloproliferative neoplasms (MPNs) or clonal hematopoiesis of indeterminate potential (CHIP). Both studies included NYSCF – Robertson Stem Cell Investigator Vijay Sankaran, MD, PhD, of Boston Children’s Hospital, who led the study on MPNs.
The Importance: These studies illuminate why certain individuals have a greater risk of MPNs, CHIP, as well as cancer or heart disease as they age. Preventing these blood cells from accumulating mutations could reduce the incidence of these deadly diseases.
MPNs and CHIP both involve an excess of blood cells, which is what set Dr. Sankaran, an expert in blood cell production, on their trail. MPNs are a class of blood cancers in which patients produce too many mature red and white blood cells and platelets, which can in turn increase risk for leukemia. Individuals with CHIP, which affects almost 10% of those over 70, do not have symptoms of disease but have excess blood stem cells, putting them at increased risk for blood cancers and heart disease.
Dr. Sankaran’s studies, carried out in collaboration with scientists at the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Boston Children’s Hospital, and Dana-Farber Cancer Institute, show that inheriting certain gene variants can cause overproduction of blood stem cells (HSCs), increasing the chances that these cells will accumulate mutations and lead to MPNs or CHIP.
“The exciting part is that for patients with either disorder, we’re starting to gain insight into why these disorders are occurring and what increases one’s risk for them. Our hope is that eventually these findings may suggest ways by which we can mitigate that risk,” said Dr. Sankaran, an associate member of the Broad Institute, an associate professor of pediatrics at Harvard Medical School, and interim chief of hematology and oncology at Boston Children’s Hospital and the Dana-Farber Cancer Institute, in a press release.
“If you can prevent the onset of these age-related mutations before they occur, you can potentially have benefits for a whole host of conditions, from cancer to cardiovascular disease,” said Pradeep Natarajan, MD, MMSc, an associate member of the Broad Institute, director of preventive cardiology at Massachusetts General Hospital, and assistant professor of medicine at Harvard Medical School, who led the study on CHIP.
Since MPNs often run in families, scientists knew that the risk for MPNs is genetically inherited, but had only identified some of the genes involved.
To fill in the blanks, Dr. Sankaran’s team examined data from nearly 3,000 MPN cases and over 800,000 controls, identifying 17 genetic variants that increase risk for MPN, 7 of which were previously unknown.
“Once we started looking at what these variants were doing, it quickly became evident to us that they were all involved in blood stem cells,” said Dr. Sankaran. “And this really gave us the opportunity to learn more about the biology of HSCs.”
Further examination revealed that people with the MPN-related variants had more HSCs that also renewed more often, and produced nearly 3x more cells than normal.
“We don’t think most of these risk variants are actually making HSCs accumulate more mutations,” said Sankaran. “They’re most likely increasing the overall pool of stem cells which affects the likelihood of one cell eventually acquiring a mutation like JAK2 V617F” (which causes MPNs).
In future studies, Dr. Sankaran will look more closely at the unique functions of each variant to understand exactly how they lead to MPNs. However, simply being aware of these new risk genes exist will help determine who may be at risk for MPN and find ways to decrease this risk.
A Variant Linked to African Ancestry Increases CHIP Risk
In the CHIP study, researchers took a closer look at the predisposing factors of CHIP and how they influence the disease, which can increase a patient’s risk of death by 40% due to blood cancer, heart attacks, and strokes.
Once again, the team turned to genetic and health data: they studied more than 90,000 people who donated data to the National Institutes of Health’s Trans-Omics for Precision Medicine (TOPMed) program, over 4,000 of which carried CHIP. Importantly, 59% of the people in this program are of non-European ancestry. This ensures that the findings are more applicable to ethnic minorities than typical studies of genetic data, which are usually heavily skewed toward those of European descent — resulting in therapies that often do not work for ethnic minorities.
Comparing the genetics of those with CHIP to those without CHIP illuminated differences in three regions of the genome, one of which was only observed in patients of African ancestry near a gene called TET2. The variant found in CHIP individuals appeared to decrease TET2 expression. Further studies in human HSCs and mice showed that decreasing or eliminating TET2 expression creates more blood stem cells — just as observed in individuals with CHIP.
“We don’t think the acquisition of mutations alone is sufficient to cause CHIP; lots of people have a mutation in a cell or a couple of cells and the cells never become more widespread,” said Dr. Natarajan. “But when you have a variant like this promoting cell growth, that makes a cell with a mutation more aggressively expand. Additionally, an increased number of cell cycles may also facilitate the acquisition of CHIP mutations.”
The researchers agree that further study is needed to determine exactly how TET2 influences HSC function and CHIP. Altogether, the studies provide a stronger understanding of two complex blood disorders driven by stem cells, which could pave the way for preventing age-related cancers and heart disease.
Inherited myeloproliferative neoplasm risk impacts hematopoietic stem cells.
Erik L. Bao, Satish K. Nandakumar, Xiaotian Liao, Alexander G. Bick, Juha Karjalainen, Marcin Tabaka, Olga I. Gan, Aki S. Havulinna, Tuomo T. J. Kiiskinen, Caleb A. Lareau, Aitzkoa L. de Lapuente Portilla, Bo Li, Connor Emdin, Veryan Codd, Christopher P. Nelson, Christopher J. Walker, Claire Churchhouse, Albert de la Chapelle, Daryl E. Klein, Björn Nilsson, Peter W. F. Wilson, Kelly Cho, Saiju Pyarajan, J. Michael Gaziano, Nilesh J. Samani, FinnGen, 23andMe Research Team, Aviv Regev, Aarno Palotie, Benjamin M. Neale, John E. Dick, Pradeep Natarajan, Christopher J. O’Donnell, Mark J. Daly, Michael Milyavsky, Sekar Kathiresan & Vijay G. Sankaran. Nature. 2020. DOI: 10.1038/s41586-020-2786-7
Inherited causes of clonal hematopoiesis in 97,691 whole genomes.
Alexander G. Bick, Joshua S. Weinstock, Satish K. Nandakumar, Charles P. Fulco, Erik L. Bao, Seyedeh M. Zekavat, Mindy D. Szeto, Xiaotian Liao, Matthew J. Leventhal, Joseph Nasser, Kyle Chang, Cecelia Laurie, Bala Bharathi Burugula, Christopher J. Gibson, Amy E. Lin, Margaret A. Taub, Francois Aguet, Kristin Ardlie, Braxton D. Mitchell, Kathleen C. Barnes, Arden Moscati, Myriam Fornage, Susan Redline, Bruce M. Psaty, Edwin K. Silverman, Scott T. Weiss, Nicholette D. Palmer, Ramachandran S. Vasan, Esteban G. Burchard, Sharon L. R. Kardia, Jiang He, Robert C. Kaplan, Nicholas L. Smith, Donna K. Arnett, David A. Schwartz, Adolfo Correa, Mariza de Andrade, Xiuqing Guo, Barbara A. Konkle, Brian Custer, Juan M. Peralta, Hongsheng Gui, Deborah A. Meyers, Stephen T. McGarvey, Ida Yii-Der Chen, M. Benjamin Shoemaker, Patricia A. Peyser, Jai G. Broome, Stephanie M. Gogarten, Fei Fei Wang, Quenna Wong, May E. Montasser, Michelle Daya, Eimear E. Kenny, Kari E. North, Lenore J. Launer, Brian E. Cade, Joshua C. Bis, Michael H. Cho, Jessica Lasky-Su, Donald W. Bowden, L. Adrienne Cupples, Angel C. Y. Mak, Lewis C. Becker, Jennifer A. Smith, Tanika N. Kelly, Stella Aslibekyan, Susan R. Heckbert, Hemant K. Tiwari, Ivana V. Yang, John A. Heit, Steven A. Lubitz, Jill M. Johnsen, Joanne E. Curran, Sally E. Wenzel, Daniel E. Weeks, Dabeeru C. Rao, Dawood Darbar, Jee-Young Moon, Russell P. Tracy, Erin J. Buth, Nicholas Rafaels, Ruth J. F. Loos, Peter Durda, Yongmei Liu, Lifang Hou, Jiwon Lee, Priyadarshini Kachroo, Barry I. Freedman, Daniel Levy, Lawrence F. Bielak, James E. Hixson, James S. Floyd, Eric A. Whitsel, Patrick T. Ellinor, Marguerite R. Irvin, Tasha E. Fingerlin, Laura M. Raffield, Sebastian M. Armasu, Marsha M. Wheeler, Ester C. Sabino, John Blangero, L. Keoki Williams, Bruce D. Levy, Wayne Huey-Herng Sheu, Dan M. Roden, Eric Boerwinkle, JoAnn E. Manson, Rasika A. Mathias, Pinkal Desai, Kent D. Taylor, Andrew D. Johnson, NHLBI Trans-Omics for Precision Medicine Consortium, Paul L. Auer, Charles Kooperberg, Cathy C. Laurie, Thomas W. Blackwell, Albert V. Smith, Hongyu Zhao, Ethan Lange, Leslie Lange, Stephen S. Rich, Jerome I. Rotter, James G. Wilson, Paul Scheet, Jacob O. Kitzman, Eric S. Lander, Jesse M. Engreitz, Benjamin L. Ebert, Alexander P. Reiner, Siddhartha Jaiswal, Gonçalo Abecasis, Vijay G. Sankaran, Sekar Kathiresan & Pradeep Natarajan. Nature. 2020. DOI: 10.1038/s41586-020-2819-2