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December 10, 2021 by Julia Gouffon, PhD 6 min read

Exploring Somatic Genetic Rescue and Pediatric MDS with Sushree Sahoo

Researcher Spotlight Series

In this Researcher Spotlight, we were fortunate to speak with Sushree Sahoo, Ph.D. from St. Jude Children’s Research Hospital in Memphis, Tennessee. Sushree specializes in translational, molecular genetics, and is passionate about uncovering the underlying mechanisms of diseases like cancer. She is the first author of a paper in Nature Medicine entitled “Clinical evolution, genetic landscape, and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes”

Julia Gouffon: You’re currently working as a postdoc doing a lot of great work at St. Jude. Can you please tell us about your research focus in general?

Sushree: On a broad spectrum, my research focuses on knowing the germline and the somatic factors that drive bone marrow failure diseases in the pediatric population. We use high-throughput genomic methods like whole-exome sequencing and whole-genome sequencing to figure out the factors that are responsible for diseases in children. Then, we create models to understand the functional impact of these factors. The aim is, that at some point, will be able to translate our insights to the clinic so that we can create therapeutic cures. We want to create strategies where we can modify the patient cells themselves — getting rid of the bad mutations and then trying to cure the patients. 

Julia: That sounds exciting. You recently published in Nature Medicine. Can you give us a little bit of background and tell us the aims of that study?

Sushree: We investigated pediatric myelodysplastic syndrome (MDS) — a disease where the myeloid population (which is essentially neutrophils, red blood cells, and platelets) are affected. It is a stem cell disorder so the cells are sick and not functional. The patient ends up with fewer myeloid cells and have empty bone marrow. 

These patients start with cytopenia,  meaning they have a lack of blood cells, and as they progress there is a huge pressure to produce more and more functional cells in the body. They then enter into a phase where they accumulate extra mutations and they can progress to other cancers like acute myeloid leukemia (AML). Then the prognosis really deteriorates. We had a cohort of patients where we wanted to see the genetic predispositions that cause pediatric MDS.

As a counterpart to pediatric MDS, adults also develop MDS, but they don’t have germline predispositions that the pediatric population has. We employed functional genomic methods like whole-exome sequencing, and we found two new genes that are germline causality of pediatric MDS: SAMD9 and SAMD9L (referred to as SAMD9/9L

The aim was divided into clinical and functional spectrums. In the clinical spectrum, we wanted to understand how these genes affect the patient’s disease prognosis, what was the overall survival of those patients who if they undergo stem cell transplantation, and what are the factors responsible for the outcome of this disease, whether it was a good outcome or a bad one.

Second, we wanted to understand what the different mutations in our patients do and how they are actually creating this bone marrow failure. Then, we wanted to correlate the presence of mutations and our patient phenotype and see how the former can inform us about the outcomes in the patient. What kind of mutations result in a very stable phenotype, and what mutations result in a phenotype that deteriorates? Or in what cases can the phenotype cure itself? We aimed to understand the whole spectrum of this disease in our study.

Julia: Your paper reports on the occurrence of somatic genomic rescue in the patients that you’ve studied. Can you expand on what this phenomenon is and its significance in patients?

Sushree: Somatic genetic rescue has been known in the world of genetics for a long time. The phenomenon occurs when a germline mutation has a negative effect, so the body employs some kind of mechanism to get rid of that bad mutation. It has two outcomes in patients: good and bad. We found out that SAMD9/L germline mutations are very toxic to the hematopoietic compartment, and as a result, the cells try to get rid of them. The mechanisms the cells employ include losing the entire chromosome that contains the mutated copy of the gene or developing a secondary somatic mutation in addition to the germline one in the same allele in order to nullify the effect of the germline mutation.

Or cells can duplicate the wild-type copy of the chromosome that contains the wild-type gene and duplicate it twice so they get rid of the mutant copy and still end up with two chromosomes. (that is chromosome 7). We call it natural gene therapy or uniparental isodisomy of 7q (UPD7q). Essentially, these are the different rescue events we saw in our patients and each rescue mechanism has its own trajectory of clinical progression. Some can make the disease worse, others can cure the disease and the patients are in remission without needing any treatment. This particular genetic mechanism was very important in the case of SAMD9/9L patients.

Julia: You included the single-cell DNA analysis as part of this research work in your study. Why is it important to assess at the single-cell level or the population of individual single cells to look for somatic genetic rescue events?

Sushree: As I said that in our patients, there is not a single rescue mechanism. There are multiple, and each one has its own trajectory of moving the disease. 

“It was really essential for us to know at the single-cell level, whether these mechanisms were interdependent on each other. We wanted to know if the events were completely random. Would we find all the rescue mechanisms in the same patient? Or would one mechanism actually inform the cause of the other? “

Another question was if they are separate or they’re interdependent, how exactly they are interacting at a single-cell level within the patient? That information will help inform us about the patient’s disease trajectories.

That’s why the single-cell study was very important  The rescue mechanism that involves the loss of a chromosome — that is a leukemic event. In these cases, cells accumulate more and more cancer mutations, and they can develop leukemia. Whereas the other rescue mechanisms can cure their disease. We really wanted to know how they are occurring within the patient.

Julia: That’s just amazing. Now that you’ve uncovered these insights into SAMD9 and SAMD9L syndrome in children, can you tell us what’s up next? What’s the next question that you would like to have answered?

Sushree: Although we found out a lot about SAMD9/9L syndromes in pediatric MDS, we don’t know much about how these genes function, They are very elusive based on their functional impact on the cells. Within every cell, each gene has its function — we still don’t know what exactly these two genes do. 

One important aspect that I want to look into is the different mutations in SAMD9/9L. These genes are accumulating so many different mutations. We had around 67 patients, and we had 58 germline mutations — you see how variable these mutations are, it’s not a single hit. This makes the gene extremely permissible to have more and more mutations. And these mutations are missense in nature, meaning they have just one nucleotide change that causes the entire disease. I want to know how those different mutations are interrelated because that information is key to how we can cure this disease without needing stem cell transplantation (which is the only curative therapy as of now).

The second thing that I am looking into is developing models, in the models where I’m employing gene editing technologies where I can figure out how I can treat the negative effects of this disease either by homologous direct recombination, where I can just switch the mutant copy with a wild type copy or by inducing other changes. If we have models, then we can use them for other diseases where somatic genetic rescue events also occur.

Julia: You are creating your own somatic genetic rescue events?

Sushree: We are modeling them. It’s more important to model them and understand what the trigger is behind the phenomenon. We still don’t know how we can induce natural gene therapy by uniparental isodisomy (duplication of the wild type copy) rather than preventing the loss of chromosome 7. Because the loss of chromosome 7 is a leukemic event that is very common in the pediatric population. It’s a poor prognostic factor and the survival rate is very low. 

We are trying to understand what causes what so that if we can amplify the uniparental isodisomy (UPD) event, it will help us to go in the trajectory of curing the disease without the need for any invasive therapy.

Julia: I think this is a really fascinating area and your insights can be utilized for so many other disease states to look at UPD.

Sushree: Since you mentioned other diseases, just to give an example, aplastic anemia is another disease where you have a severe deficiency of red blood cells. And this is very common and this involves UPD of chromosome 6 p-arm. If we can develop a technique where we can induce genomic changes in the cells — so take patient cells, do individualized gene editing, and then return them to the patient, as we do for sickle cell anemia right now. This would make a massive difference to the patient’s life and you don’t have to look for donors for transplantation.

Julia: That is very exciting news. Thank you Sushree for joining me today. I really appreciate your time. It was wonderful to hear everything that you’re doing, and we look forward to all of your future work. We hope that you will continue using the single-cell DNA analysis for the Tapestri by Mission Bio. Thanks so much.

Sushree: Thank you, Julia. It was really nice talking to you. 

“Single-cell is going to be something that, at one point we, have to use on a very regular basis because of the immense data it gives us.”


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