Rare cells capable of transforming into leukemia may provide new insight into the leukemia landscape

In our latest interview, News Medical spoke with Adam G. Schrum, PhD, associate professor of molecular microbiology and immunology and surgery at the University of Missouri-Columbia, about how dysfunction in an unusual type of thymocyte cell can develop into leukemia in some patients.

Could you please introduce yourself and tell us about your background in molecular microbiology and immunology and surgery, and what inspired your latest research?

I completed my PhD in immunology at the University of Pennsylvania School of Medicine (Philadelphia, PA, USA) and completed my postdoctoral training at the University of Basel, Switzerland.

My area of ​​study focuses on the basic immunology of infection, organ transplantation, and how the immune system develops. All of this really centers around one basic concept about the immune system that protects each individual – how does your immune system learn what exactly ‘you’ are made of? Your immune system does this job, usually very well, so when it encounters germs or viruses, it will know that this thing is not you, it does not belong in your body, and then it will destroy the thing. Even if you are implanted with parts from another person, as in an organ transplant, your immune system knows it’s not you and tries to destroy it, which is why transplant patients need immunosuppressants.

The T cells of the immune system learn what “you” are in the thymus gland, which is located almost on top of the heart under the rib cage. We were studying this process when we happened to observe a cell type in the thymus that was so small in number that we could barely detect it, but nevertheless seemed inclined to confuse the normal T-cell learning system there and instead become a type of a cancer known clinically as T-cell acute lymphoblastic leukemia. We set out to see if we could figure out what was causing this malfunction and ended up doing studies with mice and human patient samples.

According to the American Cancer Society, over 60,000 cases of leukemia (all types) are diagnosed annually in the United States. Within that number, T-cell acute lymphoblastic leukemia (T-ALL) affects more than 6,000 Americans each year. Why is it so important that research focus on why leukemia can develop in the first place?

Any clue as to what causes cancer, or disease in general, creates the possibility of being able to avoid, prevent, suppress or treat it. An obvious but important example is that when people learned that radiation causes cancer, many practices were put in place to help people avoid exposure to radiation. Another example, which in some ways is closer to our new study, was that when gluten was identified as an immune stimulant for celiac patients, diets were changed to avoid this cause and improve the lives of the patients. The gluten stimulant comes from a small chopped piece of gluten bound in a protein called human leukocyte antigen (HLA) in humans, or more commonly Major Histocompatibility Complex (MHC).

This is where our research ties in. The surprising causative culprit for T-ALL cancer in our study was MHC. It is possible that this causal pathway leading to this cancer does not apply to most cells in the thymus gland, but rather to only some rare, subtle cells that we observed doing this.

It is no exaggeration to say that MHC (or HLA in humans) is probably one of the most famous molecules in immunology, with more than one Nobel Prize awarded for breakthroughs in its understanding. MHC is like a garbage can with the lid off, up on the surface of every cell, and T cells can spend decades going from one cell to another, scanning what’s in the garbage. MHC always presents small particles of the proteins you are made of in it. Usually, the trash is full of pieces of your stuff. But if something harmful or foreign is found in your garbage, your T cells sound the alarm, say that there are particles in your MHC garbage can that are not you, and they mobilize your immune system to destroy your cells and the things around this evidence.

It’s unhealthy if this process goes awry, such as when celiac patients overreact to the little gluten in their MHC, or when autoimmunity patients see their immune system’s T cells mistakenly react against their body’s own ingredients, when everything, which must have is tolerated without an immune reaction. Now, our study sees a similar process occurring when T cells are supposed to be at school in the thymus gland, learning how to distinguish themselves from anything foreign. It appears that there is a cell there, in small amounts in humans and in mice, that may be susceptible to an incorrect MHC response, this time turning into cancer. If we can learn more about what’s going on there and whether certain small particles are represented in the MHC dustbin, we may learn about a new molecule to avoid.

Another possible lesson to be learned is that if such a subtype of this T-ALL cancer is identified early enough, it is possible that some existing drugs that inhibit MHC-dependent signaling in normal T cells may merit consideration for application here ( but we don’t know that yet).

Can you tell us more about T-cell acute lymphoblastic leukemia and the current treatments used to target it?

Current treatments often include radiation therapy and chemotherapy. In fact, it can have a pretty good cure rate compared to other cancers, especially in pediatric patients. There are other trials of therapies in development, including CAR-T cells, where it is hoped that huge progress can still be made. The most important therapeutic barrier to overcome will be (1) in children whose cancer relapses after therapy, where response rates are currently much lower, and (2) in adult patients, where an even rarer cancer, but when detected, lacks the favorable response probability seen in children.

Your study first began by examining mice with T-ALL. Can you tell us more about how you conducted the research and the findings you found in human samples?

We first detected the tumors in experimental mice, and these observations pointed us to the barely detectable cell type that appeared to be causing the cancer. After seeing this, we looked at normal human pediatric thymus and found that the cell type was also present and also barely detectable. This, in turn, led us to seek whether cancer patterns could be observed in clinical human samples from patients with this leukemia.

At our local academic hospital at the University of Missouri-Columbia, there were five pediatric cases over a three-year period, and when we looked at their clinical samples, we found that one appeared to be the subtype that we identified. Of course, much more work will be needed in the future with larger numbers of samples and possibly multicenter participation to be able to learn the prevalence of this. But at least we have learned that this process appears to be represented across the spectrum of human disease. We have learned that this is worth pursuing and plan to continue our research in this direction.

One of the most exciting findings from the study is that although EADN cells may not be responsible for all cases of T-ALL, the cells identified may be responsible for some cases of this type of cancer. Looking to the future, how do you think further research can help to better personalize treatment for patients with T-ALL?

Identifying cancer subclasses could lead to drug optimization and personalized treatments that could better respond to the specifics of each person’s disease. Discoveries like this can lead to the invention of new drugs and treatments, and we all hope that this is the case in general. But even with existing drugs and therapies, there is a lot of variation in a patient population, with some responding well to treatment, some responding little, and some responding little or not at all. Part of this happens because we lump together many subtly different diseases under one name. But with the advent of studies like this, we’re learning more and more about how to subclassify and stratify and distinguish important nuances of difference between diseases, in this case leukemia.

The more markers we can identify in the leukemic landscape, the better we will learn our way, and it is my belief that the progress made will continue to make positive improvements in personalized treatments.

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About Adam G. Schrum

I am an associate professor of molecular microbiology and immunology, surgery, and bioengineering at the University of Missouri-Columbia School of Medicine and College of Engineering.