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April 28, 2021 by Julia Gouffon, PhD 4 min read

Ross Levine Leverages Single-cell Multi-omics to Probe AML

Researcher Spotlight Series

On AML World Awareness Day (April 21), we were honored to speak with Dr. Ross Levine, MD from the Memorial Sloan Kettering Cancer Center. Ross aims to better understand the genetic basis of myeloid malignancies and recently published a Nature paper: “Single-cell Mutation Analysis of Clonal Evolutions of Myeloid Malignancies.” We chatted with Ross about his career in science, AML awareness, and how single-cell multi-omics is shining a brighter light on cancer.

Julia Gouffon: Can you tell us a little bit about yourself and how it is that you became interested in hematological oncology?

Ross Levine: It’s a great question. I went into medicine not really ever thinking I’d be a scientist. And when I was in medical school, mostly because you have that one summer between first and second year, I decided to go to the lab because I should probably learn a little bit about molecular biology. And I got hooked. It was a cancer genetics lab and that really inspired me. And I’ve always found that an interesting area — the area of cancer genetics. That followed me into my clinical training. Then I really saw leukemia as an area where I enjoyed the clinical aspect. And yet there were important questions about genetics and genomics. And I’ve been stuck ever since.

Julia: Today is the AML Awareness Day. And in light of the Nature paper where you use single-cell multi-omics to investigate this disease, what new insights did you find? 

Ross: The way I think of it is that the use of single-cell DNA and DNA + protein profiling allowed us to do a couple of things. The first one was to really look at AML not as one monolith, but rather as a menagerie of different cells and clones. And really, for the first time, do that [analysis] on a large number of samples for any cancer. I think that was important.

You can see all that, but what does it mean? And for us, a lot of it was really showing a couple of key features. The first was showing you can map out the sequential trajectory of mutations, look at the relative fitness of different clones, and at dominant versus minor subclones. All of those features come that you could never get out of bulk sequencing and really the data, although that may have been the most important thing, was the start. And then we began to look at things like cell surface [protein] versus DNA, but that was really just a taste of what you can do with that— the idea of linking cell state. And we’re excited about what is coming, not just what we did.

Julia: You’ve previously noted that your research is really translational in focus. And so how does the work in the lab translate into how you make decisions in the clinic and how you use this to inform therapeutic selection in your patient population?

Ross:  We’ve now for more than 10 years been very interested in asking:

“Can we use genomics as a way to make clinically important decisions for our patients?”

And we published a paper nine years ago showing that bulk genomic profiling can be used to prognosticate AML and make therapeutic decisions. And many groups have taken that to the next level. So obviously the first and most important thing is we use genomics every day when I’m in a clinic.

The question I think in front of us for the future is how do we use single-cell DNA sequencing in the clinic? I don’t think we’re there yet, but…

…”it’s my hope that as we generate enough data as a field and we can figure out how single-cell DNA gives us hints into who responds, what drugs we should or shouldn’t use, we’re going to learn how to use it, and then within a year or two we’ll be using it.”

It took us five years to get functional profiling — from “not at all” to at Sloan Kettering or Stanford — to everywhere. And I think single-cell will be like that. I am hopeful that in the next 12 to 18 months, we and few centers will start showing how it can be specifically useful in particular circumstances. And then it will really broaden and deepen. And we’ll be excited to work with everybody out there.

Julia: We’re looking for you and other groups to continue these clinical utility studies using our platform and advancing the science. In the future, is there any question that remains about AML or other myeloid malignancies that you’re thinking about tackling using this technology?

Ross: I think there’s a lot we don’t understand. I think one is the issue of looking at specific subtypes, like p53 mutant disease. In the past, because we couldn’t enumerate copy number alterations with the panel we designed, you couldn’t look at the architecture of p53 mutant disease karyotype. So we’re very excited about that. And likewise looking at things like translocations as well, and layering the core architecture there. If you look at our study, it was largely focused on normal karyotype intermediate-risk AML, so neither fusion protein nor p53-[mutant]. So I think that’s the next obvious thing that needs to be done.

I think that on a broader level, the idea of looking at larger sets of surface markers, or maybe other multi-omics, with mutations will let us look at clone-specific biological features. And if we can understand how different clones are different from each other and from normal and in as many ways as possible that will give us the insights, I think, to drive the mechanistic and therapeutic science, which I’m really excited about.

Julia: I know you just gave a talk and are probably heading back to the Keystone e-symposium, or maybe to your clinic this afternoon.

Ross: I’m chairing the Keystone Hematopoiesis [conference] and hopefully people are joining us for that. I think cramming it all in today, especially on  AML World Awareness day feels like just the right thing to do.

Julia: Well, thank you so much for taking the time to speak to us today. It’s so nice to have you as part of the Mission Bio research team that is making an impact in the lives of all of the hematological patients out there in the world. So thank you very much for joining us today.

Ross: Thank you so much.

Interested in hearing more about Dr. Ross Levine’s research? Watch his on-demand webinar.

If you are intrigued by single-cell multi-omics, check out our single-cell 101 ebook!

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