Acute myeloid leukemia (AML), a cancer of the blood and bone marrow, is usually only diagnosed at an advanced stage, at which point it requires aggressive treatment. Although AML is a relatively rare disease, accounting for just 1.8 percent of cancer deaths in the U.S., its incidence is expected to increase as the population ages. The average age of diagnosis is 68.
“What’s horrible about AML is that often there are no symptoms or very mild symptoms, and it’s discovered during a routine blood test, meaning it’s identified when it is at a very late stage,” says Dr. Liran Shlush of the Weizmann Institute of Science’s Department of Immunology.
An MD/PhD who specializes in hematology, Dr. Shlush first became interested in the challenges of treating leukemia during a residency in internal medicine at Rambam Medical Center in Haifa.
“I continuously saw leukemia patients dying and I realized that leukemia treatment hadn’t changed much for the past 50 years, and we needed a transformation,” he says. “I wanted to understand how we could identify and treat leukemia earlier, and maybe prevent it.”
Following his residency, Dr. Shlush pursued both postdoctoral research and a clinical fellowship in the leukemia program at the Princess Margaret Cancer Center at the University of Toronto. It was during his postdoc that Dr. Shlush had a major insight into the biology of AML.
The blood tests could identify patients at risk for AML as many as eight years before diagnosis – and with virtually 100% accuracy.
By tracking the “family history” of individual cells from the blood of AML patients, and using a method known as deep sequencing to identify alterations in genes commonly mutated in the disease, he and his collaborators were able to identify – for the first time – “pre-leukemic” stem cells: mutants that will divide and, after many years, form cancerous cells while acquiring more mutations. Nature Medicine named this one of 2014’s most notable advances in medicine.
Since joining the Weizmann Institute in 2016, Dr. Shlush has launched an ongoing study called WizeAging that looks at how and under what conditions genetic changes in blood cells may affect our health as we age. He and his team are recruiting volunteers over the age of 50 who take a blood test once a year for 10 years. They are looking for mutations in the DNA of the volunteers’ white blood cells that may predict age-related conditions such as blood diseases and blood cancers, including leukemia, as well as other cancers, heart disease, and diabetes. Dr. Shlush believes that these common diseases of aging may all have roots in changes in the immune blood cells, and the results of this research could have a profound impact on the early detection of numerous diseases.
In a 2018 breakthrough that was published in Nature, Dr. Shlush made important progress towards his goal of early diagnosis and treatment for leukemia. He and his colleagues started with information from a large European database in which 500,000 people had the DNA from their blood cells stored and were then followed for 20 years, during which time a few developed AML. Working backward from the cancer cells to the blood cells of the patients before the disease was diagnosed, the scientists pinpointed a set of early mutations in the AML patients, and observed that the cells carrying these mutations were also the ones that multiplied more rapidly later on.
Dr. Shlush’s research could lead to the development of blood tests that will identify diseases – including common diseases of aging – long before symptoms appear.
Using this knowledge, the team framed a set of rules that, when applied to the earlier blood tests, could predict who would eventually be diagnosed with AML. In fact, the at-risk patients could be identified as many as eight years before diagnosis, and with virtually 100% accuracy.
Dr. Shlush is currently collaborating with Memorial Sloan Kettering Cancer Center in New York City and the Clalit Research Institute in Israel to develop the first clinical trial for the prevention of AML based on a specific mutation that affects the cells’ ability to make certain proteins. The ultimate goal is to identify a treatment that will slow or prevent the disease, and the team will be testing an on-the-market medication for its effectiveness against AML in high-risk patients. “We know this drug is very safe and think that it could shrink the precancer stages,” says Dr. Shlush. “We predict that this approach will be very, very useful for slowing the development of the disease.”
“Because of the Weizmann Institute of Science, this dream I’ve had for years to screen the population and identify leukemia early is becoming real now,” he says.
Although it’s not currently practical to have everyone over 50 undergo genetic testing for a rare disease like AML, Dr. Shlush is working with Prof. Amos Tanay of the Institute’s Department of Computer Science and Applied Mathematics and Department of Biological Regulation and Prof. Ran Balicer from Clalit to develop an algorithm that would point to those people who, based on the blood tests in their medical records, would be at risk for AML. This narrowed-down group could then undergo more specialized DNA testing. Clalit Health Services is Israel’s largest HMO, and the team is using Clalit’s database, which contains 4.5 million electronic health records, for this research.
Dr. Shlush credits his colleagues at the Weizmann Institute with making this work possible, and the partnership between Clalit and Weizmann has given him access to this vast database and a chance to apply his finding to treating patients.
The research of Dr. Liran Shlush is supported by the Sagol Institute for Longevity Research; the Barry and Eleanore Reznik Family Cancer Research Fund; the Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders; the Rising Tide Foundation; and the Applebaum Foundation. He is the incumbent of the Ruth and Louis Leland Career Development Chair.
