What can green lizards and “dark matter” teach us about cancer?
First a bit about genomic dark matter: It refers to DNA sequences that make up a large part of the human genome but do not encode proteins, some of which are known as IncRNAs. They play a role in tissue development, tumor formation, and cancer progression—but many key questions remain about dark matter and IncRNAs.
University of Rochester Medical Center scientist Bin Zhang, Ph.D., and a team of researchers discovered how IncRNAs function and evolve in the genomes of green lizards. Their work is published in Cell Reports, in collaboration with scientists at Cold Spring Harbor Laboratory, Long Island, N.Y., where Zhang worked before joining URMC in 2015.
One particular IncRNA—MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1)—was first associated with lung cancers that were likely to spread and later found to be over-abundant in many other tumor types. The MALAT1 gene contains a unique tail structure that stabilizes the RNA molecule. Zhang’s team pioneered a series of computer models and algorithms allowing them to turn the tail structure into a searchable module. They discovered a class of 130 different vertebrate IncRNAs with similar structures to MALAT1, and then further conducted evolutionary studies into the activity of the IncRNAs in green lizards. The National Cancer Institute and National Institute of General Medical Sciences funded the study.
An assistant professor in Pathology and Laboratory Medicine and Pediatrics, Zhang also specializes in clinical cytogenetics and molecular genetics. He conducts detailed genetic tests and evaluates blood, bone marrow, lymph nodes, and other tissues for cancer.
Leukemia is one of the hardest cancers to treat, but scientists have discovered a new, targetable pathway in one of the worst subtypes of the disease.
The study, although only relevant in mice and human cell cultures at this point, is important because researchers found that an existing drug, known as creatine kinases inhibitor, is effective at attacking acute myeloid leukemia (AML) in the laboratory.
University of Rochester Medical Center and Wilmot Cancer Institute scientists Archibald Perkins, M.D., Ph.D., and Yi “Stanley” Zhang, Ph.D., teamed up with researchers at Harvard University and the Massachusetts Institute of Technology to study a particular gene, EVI1. When this gene is active, certain types of leukemia and some solid tumors, such as ovarian cancer and some breast cancers, are virtually untreatable.
Their study recently was published in the high-impact journal Nature Medicine. The group showed that when EVI1 is abundant in leukemia, it changes the metabolism of immature blood cells as they progress toward becoming cancer—but also leaves EVI1-positive cancers vulnerable to treatments that can strike down that pathway.
The Perkins/Zhang laboratory in the Department of Pathology and Laboratory Medicine has been investigating the EVI1 gene for several years, resulting in a solid track record of publications on the topic. Their goal is to discover new treatments that will target the underlying pathways involved in EVI1-positive cancers. The Perkins/Zhang data supported Harvard’s and MIT’s investigation of what drives the EVI1 gene.
Leukemia is a type of blood cancer in which abnormal blood cells crowd out the healthy white blood cells responsible for fighting infection. More than 10 different major subgroups of leukemia exist. Many types of leukemia are resistant to treatment, although some patients with AML and other blood cancers can achieve long-term remission if they qualify for a stem cell transplant. Wilmot’s Blood and Marrow Transplant Program is the only program in the Finger Lakes region to offer that therapy.
The Nature study was recently highlighted by the American Association of Cancer Research. Perkins and Zhang are working on other leukemia studies as well, supported in part by Wilmot seed funds and by the URMC Clinical & Translational Science Institute.