Blood Cancer
Predicting – and Preventing – Blood Cancer? An Essential Conversation.
Grant Challen, Ph.D
Associate Professor, Department of Medicine Oncology Division and Stem Cell Biology Washington University School of Medicine in St. Louis
A recent recipient of funding from The Longer Life Foundation, Dr. Grant Challen, Associate Professor Department of Medicine, Oncology Division and Stem Cell Biology at Washington University School of Medicine in St. Louis, leads a lab studying ways to identify genes that can be targeted to diagnose blood cancers early – or even recognize the risk before they develop. RGA’s Dr. Daniel Zimmerman, Managing Director, Longer Life Foundation, spoke to Dr. Challen about why blood cancers can be so difficult to treat and what his novel research seeks to accomplish.
Q:
Dr. Zimmerman: To understand strategies to prevent disease, we first need to understand causes. What should people understand about how blood cancers develop?
A:
Blood cancers are caused by genetic mutations that happen mostly as a consequence of aging. To repopulate our blood and to divide and replicate blood cells, bone marrow stem cells must copy the entire genome and all of the nucleotides of the DNA sequence. In general, this cell machinery does a really fantastic job, but over time, in each cell division one or two mistakes happen across the 300+ billion DNA nucleotides in a genome.
This process resembles making a photocopy. Every time you make a copy there are subtle variations from the original. For the majority of us, these mutations will be inconsequential. They happen in areas of the genome that don’t matter or in genes that are not important for those cells to function. Very rarely those errors occur in genes that are critical to the functioning of blood stem cells. When the error occurs in cancer-causing genes, it leads to the cell having what we call a competitive advantage over its normal counterpart cells in the bone marrow, which causes it to grow exponentially and start to overtake the bone marrow. This first stage of blood cancer is called clonal hematopoiesis.
Clonal hematopoiesis is a function of age because every time that stem cell divides, you increase the likelihood of getting a mutation in a particularly important cancer-causing gene. As we age, all of us will develop some level of clonal hematopoiesis with mutations in cancer causing genes. The good news is that for 99.9% of us, it won’t matter. We are trying to understand what makes that small fraction of the population who do get blood cancer different from the rest of us who will go on to live normal healthy lives into old age.
We are trying to understand what makes that small fraction of the population who do get blood cancer different from the rest of us who will go on to live normal healthy lives into old age.
Q:
Dr. Zimmerman: What role does the environment or family history of cancer play in contracting blood cancers?
A:
Only two kinds of cancer are proven to result from external factors – smoking, which causes lung cancer, and sun exposure, particularly ultraviolet rays, which causes melanoma.
We can inherit from familial or family predisposition some forms of cancer. But for the vast majority of blood cancers, I would say for over 95%, contracting these diseases is just bad luck. There’s really nothing that an individual can do to avoid this.
Q:
Dr. Zimmerman: Talk about your research to stop the progression of blood diseases.
A:
Our goal is to identify exactly how specific mutations that occur in important genes in our blood change the fundamental properties of stem cells. These changes lead mutated cells to be able to out-compete normal cells and establish what we call clonal dominance – or clonal hematopoiesis.
If we can drill down and understand the molecular machinery and find pathways that the mutant cells rely on for this increased growth advantage, we can come up with some effective therapeutic strategies to target these stem cells. I think of it as a kind of molecular weed killer, where we are weeding out the cancer-causing cells from the patient’s bone marrow and leaving the normal cells intact.
Q:
Dr. Zimmerman: Does your lab have unique expertise in this research field?
A:
Yes, our lab had identified a particular gene that seemed important for stem cell function called DNMT3a. Mutations occur here in approximately 20% of AML cases. Basically this is an enzyme that regulates the epigenome and tells your DNA which genes to express.
We found that this gene was particularly important for blood stem cell function. At the same time as this work from our lab-based studies was being published, sequencing studies at Washington University identified this gene as being one of the most recurrently mutated genes in adults with acute myeloid leukemia. Thanks to support from The Longer Life Foundation, we are now looking for ways to specifically weed out these stem cells with DNMT3a mutations from the bone marrow of people.
Q:
Dr. Zimmerman: Do you foresee a day, maybe when we turn 65 and as part of our regular check-ups, we could get a test that might screen us for these abnormalities, and if we’re at risk, we could get preventative therapies?
A:
Our goal is to identify exactly how specific mutations that occur in important genes in our blood change the fundamental properties of stem cells. These changes lead mutated cells to be able to out-compete normal cells and establish what we call clonal dominance – or clonal hematopoiesis.
If we can drill down and understand the molecular machinery and find pathways that the mutant cells rely on for this increased growth advantage, we can come up with some effective therapeutic strategies to target these stem cells. I think of it as a kind of molecular weed killer, where we are weeding out the cancer-causing cells from the patient’s bone marrow and leaving the normal cells intact.
Q:
Dr. Zimmerman: When do you see this being available to physicians?
A:
As I mentioned, we’re all acquiring cancer-causing mutations in our bone marrow as we age, but the vast majority of people are going to be just fine. It’s in the very rare fraction of individuals who progress from mutations to leukemia. So, two key developments are critical to our making preventative therapies a reality. First, we need to develop a greater understanding of the specific genes in the particular variants that are involved in developing blood cancer, and second, we need to understand the environmental factors and family histories that might separate an individual from the 99.9% of us where mutations don’t matter.
These studies are happening now. We are looking at retrospective analysis of epidemiological cohorts in patients whose samples have been banked for a number of years – even decades. We are determining which of those patients developed blood cancer. We can then backtrack and analyze what might have happened for each cancer patient that resulted in that person developing leukemia, for example. We can use that information to answer questions about which patients within the general population may be more at risk of developing blood cancers.
A number of researchers are looking for answers to these questions. Scandinavian countries have done a great job of cataloguing large cohorts of individuals whom they follow over time. Large databases offering patient information are coming online now, like the UK Biobank. I feel that over the next five to 10 years, this part of our knowledge base will be more complete. We will have surveyed enough people across the globe in the general population to say with a fair degree of accuracy that this person will have say a 90% chance of developing leukemia over the next five years based on his or her mutational history.
What should we do to address the risk? That is really where the laboratory-based studies help us because we use the molecular tools developed in the lab to understand how these mutations change fundamental properties of the stem cells and lead us to a way that we can target them.
So in our lab, we use a combination of cell lines from mice that we genetically engineered to carry the human mutations and primary human patient samples to run a lot of different screens and diagnostic tests. We can use these to run multiple different screens and diagnostic tests to try and figure out what sensitivities these mutations might carry for the cells that are not also carried by the normal cells in our bone marrow. The goal is to identify non-cytotoxic therapies that we could use to treat people by weeding out their mutant stem cells and reducing their lifetime risk for developing leukemia.
Q:
Dr. Zimmerman: This is something for insurers to watch.
A:
This will never be an absolute all-or-nothing benefit. We are never going to be able to absolutely say that your chances have gone from 90% to zero because it is all probability. It is all statistics. We are just trying to tilt the scales back in the patient’s favor by developing what I call precision intervention.
Meet the Investigators
Blood Cancer
Grant Challen, Ph.D
Predicting – and Preventing – Blood Cancer? An Essential Conversation.
A recent recipient of funding from The Longer Life Foundation, Dr. Grant Challen, Associate Professor Department of Medicine, Oncology Division and Stem Cell Biology at Washington University…
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