Mount Sinai-Led Team Builds First Model of the Progression of Acute Myeloid Leukemia using CRISPR
Could Help Identify Early-Stage Therapeutic Targets
A research team led by the Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai) has built the first cellular model to depict the evolution of acute myeloid leukemia (AML), from its early to late stages. By using gene editing technologies to alter genes that make cells malignant, the team was able to identify potential therapeutic targets for early disease stages. The study was reported in the journal Cell Stem Cell in February.
The therapeutic targets could be applicable not just to AML but also to the blood cancer myelodysplastic syndrome and clonal hematopoiesis, which is often a preleukemic condition.
“We essentially built from scratch a model of leukemia that characterizes the molecular changes that underlie progression of the disease, and which allowed us to identify the earliest events in its development that can be therapeutically targeted,” said Eirini Papapetrou, MD, PhD, Associate Professor of Oncological Sciences at Icahn Mount Sinai, and senior author of the study. “By creating the first cellular model to track the evolution of human leukemia, we believe we’ve taken an important step toward unraveling the cellular biology of this disease. We’ve identified molecular vulnerabilities that occur early in the disease process which could potentially lead to improved biomarkers and novel treatments for AML—goals that have proven so elusive to medical science in the past.”
AML is a cancer of the blood and bone marrow, the spongy tissue inside bones where blood cells are made. The disease, which primarily affects white blood cells, is one of the most common leukemias in adults, with more than 20,000 newly diagnosed cases each year in the United States. While several new drugs have been introduced in recent years targeting the disease, they have fallen short of significantly changing patient outcomes or survival.
By introducing specific leukemia-causing gene mutations through CRISPR-mediated gene editing, Icahn Mount Sinai researchers were determined to better understand the successive stages of the evolution of leukemia. CRISPR is a powerful tool that allowed the team to alter the DNA sequences in induced pluripotent stem cells (iPSCs) to create a model with an increasing number of mutated genes that shows progressive malignant features that correspond to their human counterparts in myeloid disease. CRISPR gene editing uses Cas9, an enzyme that acts like a pair of molecular scissors with the ability to cut strands of DNA. Through use of these tools, the researchers were able to recapitulate the step-by-step conversion of a normal cell into a malignant one.
“CRISPR/Cas9 and iPSC technologies gave us the unique opportunity to characterize changes underlying the transitions between stages of AML, and to harness patterns of these changes to pinpoint target genes for early intervention,” explains Dr. Papapetrou.
Specifically, the researchers found that inflammatory and innate immunity pathways constitute such early targets and demonstrated that inhibitors of these pathways, therapies that are being trialed in blood cancers and immune-related disorders, may be promising therapeutic modalities for AML and myelodysplastic syndrome.
Other partners in the study included Memorial Sloan Kettering Cancer Center in New York, and Cincinnati Children’s Hospital Medical Center.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report's "Honor Roll" of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children's Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.