UChicago-led team creates potential new approach for early detection of blood cancer

Bone marrow from an older woman with mild macrocytic anemia and subtle dyserythropoiesis and occasional ring sideroblasts. (Courtesy of Andrew Artz and John Anastasi)

Bone marrow from an older woman with mild macrocytic anemia and subtle dyserythropoiesis and occasional ring sideroblasts. (Courtesy of Andrew Artz and John Anastasi)

New research published Monday in the Proceedings of the National Academy of Sciences may eventually help doctors diagnose myelodysplastic syndromes, a group of blood disorders, earlier and without performing an often-painful bone marrow biopsy.

About 13,000 patients are diagnosed with myelodysplastic syndromes, known as MDS, in the U.S. each year. These disorders, characterized by low blood cell counts, can ultimately lead to acute myeloid leukemia.

Wickrema lab3

Amittha Wickrema, PhD, professor of medicine

“This new approach can be potentially used in diagnosing MDS at very early stages,” said Amittha Wickrema, PhD, professor of medicine at the University of Chicago. “That’s better than the current standard where a clinical pathologist is needed to make that determination by visually examining the bone marrow biopsy, which is typically performed at an advanced stage of the disease. One of the advantages of the potential new approach is that it can detect subtle abnormalities in the cell structure before they manifest as MDS.”

Wickrema, who is also the director of the clinical cell therapy laboratory at the University of Chicago Medicine, conducted the research along with the laboratories of Amit Verma, MBBS, from Albert Einstein College of Medicine and Montefiore Health System, and Todd Evans, PhD, from Weill Cornell Medical College. Other University of Chicago collaborators on the study include Michelle Le Beau, PhD, Arthur and Marian Edelstein Professor of Medicine and director of the University of Chicago Medicine Comprehensive Cancer Center, Andrew Artz, MD, associate professor of medicine, and John Anastasi, associate professor of pathology.

The investigators found that a protein called DOCK4 is needed to maintain red blood cell shape and “overall nuclear morphology” in healthy, developing red blood cells. Low levels of DOCK4 lead to abnormally shaped red blood cells, much like those seen in MDS patients. By discovering the importance of DOCK4, the group found that it is responsible for the formation of an undisrupted actin skeleton – a scaffolding that is critical for maintaining the red blood cell’s shape.

The UChicago research team developed a new, sensitive method for precisely calculating the extent of actin skeleton disruption in blood cells using multispectral flow cytometry technology. This high-throughput approach allows researchers to quickly characterize single cells by their size and shape and accurately sort them. This novel method could provide a sensitive, non-invasive way to diagnose MDS.

Wickrema - PNAS

Scientists aren’t sure what causes patients to develop MDS, but risk factors include being previously treated for cancer with chemotherapy or radiation, certain inherited genetic conditions and exposure to certain chemicals and heavy metals. Patients with MDS are typically treated with medication, chemotherapy and stem cell transplants.

Identification of DOCK4 as a gene lost or silenced in MDS, and uncovering the impact of reduced DOCK4 expression on developing red blood cells, provides one important clue about how MDS arises.

Other researchers involved in the study are: Sriram Sundaravel, Ryan Duggan, David L. Ebenezer, Hui Liu and Subhradip Karmakar from the University of Chicago; Tushar Bhagat, Yiting Yu, Matthias Bartenstein, Madhu Unnikrishnan and Ulrich Steidl from the Albert Einstein College of Medicine; Ting-Chun Liu, Ingrid Torregroza and Thomas Quenon from Weill Cornell Medical College; Kathy L. McGraw and Alan F. List from Moffitt Cancer Center; Andrea Pellagatti and Jacqueline Boultwood from the University of Oxford; and Vijay Yajnik from Massachusetts General Hospital.

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