Single-Cell Study Sheds Light on Leukemia’s Family Tree

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Postdoctoral fellows Linde Miles and Robert Bowman in the lab.

Postdoctoral fellows Linde Miles (left) and Robert Bowman are learning more about genetic changes that lead to cancer in blood cells.

When Memorial Sloan Kettering postdoctoral fellows Linde Miles and Robert “Bobby” Bowman began working on a new research project in May 2019, they didn’t know how massive a task it would be.

Now, their undertaking — the biggest study ever to examine the genetic causes of leukemia at the level of individual cells — is being published October 28, 2020, in Nature. The findings reveal how a series of mutations in normal blood cells can lead to them eventually becoming cancerous. The study also shows how these mutations accumulate as the disease progresses.

“This single-cell approach gave us new insights into the journey that blood cells take on their path to becoming leukemia,” says physician-scientist Ross Levine, senior author of the paper and a member of the Human Oncology and Pathogenesis Program. “Our hope is that this glimpse into how and why leukemia develops will open up new areas of research in early diagnosis and treatment.”

Learning about Cancer, Cell by Cell

Traditional genomic analysis of cancers — including MSK-IMPACTTM, a test that looks for mutations in 468 genes in patients’ tumors — uses what is called bulk sequencing. That means that it surveys the mutations that are present across all the cells in a tumor sample.

By contrast, the approach used in this study deciphered the mutations found in every single cell. The samples were obtained from 146 people who were treated at MSK for acute myeloid leukemia (AML), as well as those with two blood conditions that can lead to AML: clonal hematopoiesis and a blood cancer called myeloproliferative neoplasms. The analysis yielded data on nearly 750,000 unique blood cells.

[This is] probably the most collaborative project I've ever worked on.
Linde Miles postdoctoral fellow

“Instead of just broadly profiling all leukemias, we wanted to be able to ask pointed biological questions,” Dr. Bowman explains. “Understanding how these mutations work together will give us insight into their biological function.”

One aspect the study focused on is what’s called the clonal architecture of the cancer. This is the order in which the mutations occur. Dr. Levine compares it to a family tree, with each branch taking the cells in a different direction — some remain healthy and others become aggressive cancer.

“Trying to figure out the clonal architecture is like looking at a maze,” says Dr. Miles, a biochemist who was recently awarded a Marie-Josée Kravis Women in Science Endeavor (WiSE) fellowship. “It required a lot of work to begin to make sense of what we found and begin to detect patterns.”

Meet Linde Miles, Winner of a Kravis WiSE Postdoctoral Fellowship
Dr. Miles is a postdoctoral fellow in the Human Oncology and Pathogenesis Program at MSK studying the genetics of blood cancers.
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A United Effort

Dr. Miles spent the summer and fall of 2019 sequencing patient samples. She was able to complete five or six samples a day. When she finished, the amount of data that had been generated was overwhelming.

As a computational biologist, Dr. Bowman’s role was to figure out which mutations occurred together in the same cells and determine the order in which they appeared. At one point, he decided to consult his younger brother, Michael Bowman, a PhD student in mechanical engineering at the Colorado School of Mines.

Michael helped the MSK team develop the right mathematical formulas with an approach he normally uses to study robot behavior. Eventually he came to visit New York City, and spent much of the time that was supposed to be a vacation pouring over data with his brother, Dr. Miles, and Dr. Levine. Michael Bowman is a co-author on the paper.

“This was very much a team effort, and Ross was involved at every step, too,” Dr. Miles says. “It’s probably the most collaborative project I’ve ever worked on.”

Understanding how these mutations work together will give us insight into their biological function.
Robert Bowman postdoctoral fellow
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Building a New Playbook for Cancer Research

Dr. Levine says the goal of this work is to take the new information about the clonal architecture back to the lab and use it to create more accurate disease models that can then be deployed to develop new diagnostic methods and potentially test new drugs.

“The analogy I like to use is that cancer is like the Death Star in Star Wars,” he says. “You can’t take it apart until you know where the critical nodes are — where the cells are most vulnerable to attack.”

He also explains that, historically, leukemia research has led to methods that can be used to study many other cancers. “Because we can get leukemia samples with a simple blood draw, they’ve always been more accessible,” he says. “Our hope is that similar single-cell studies in solid tumors and other blood cancers will follow and that our work will provide a playbook on how to approach these studies with other kinds of cancer.”

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This research was funded by National Institutes of Health and the National Cancer Institute grants P30 CA008748, K99 CA248460, K08 CA241318, K08 CA215317, R37 CA226433, P30 CA056036, R35 CA197594, and R01 CA173636. It was also supported by the Leukemia and Lymphoma Society, the Sohn Foundation, the Damon Runyon Cancer Research Foundation, the Swiss National Science Foundation, the American Society of Hematology, the Edward P. Evans Foundation, the Concern Foundation, the Sidney Kimmel Cancer Center, Cycle for Survival, and the Samuel Waxman Cancer Research Foundation.

Dr. Miles has received travel support and honoraria from Mission Bio.

Dr. Levine is on the supervisory board of QIAGEN and is a scientific advisor to Imago, C4 Therapeutics, Mission Bio, and Isoplexis. He was also a scientific advisor to Loxo Oncology until February 2019. He receives research support from and has consulted for Celgene and Roche and has consulted for Lilly, Jubilant, Janssen, Astellas, Morphosys, and Novartis. He has received honoraria from Roche, Lilly, and Amgen for invited lectures and from Celgene and Gilead for grant reviews.