Imagine two teams of detectives investigating two crime scenes. In one case, still photographs detail extensive property damage, but offer few clues about the culprit, the method, or the motive. Across town, in a similar case, video footage captures the actual crime, allowing the police to study the order of events leading up to the present, simply by rewinding the tape.
The difference in the of bodies of evidence could be the key to solving the crime. It could also be the difference in developing new clues about an increasingly prevalent health challenge linked to fatal forms of cancer.
Myelodysplastic syndromes (MDS) are heterogenous blood disorders that affect up to 170,000 people in the United States, primarily over the age of 60. While early symptoms, including anemia (characterized by fatigue), are not serious, MDS is a high-risk factor for leukemia. Currently there are few treatment for MDS and the causes remain poorly understood.
Right now, for example, researchers hoping to understand the onset of MDS rely primarily on the diagnostic equivalent of the still shot – a genomic test that reveals which mutations are present in a patient’s blood cells, but not how (or in what order) the mutations occurred, giving them little insight into what happened or how to prevent it from happening again.
Dr. Sergei Doulatov, an Assistant Professor of Medicine and Hematology, and a faculty member of the Institute for Stem Cell and Regenerative Medicine (ISCRM), is determined to help change that. Research reported in a new paper published in the journal Blood, the first for the Doulatov Lab, details how his lab is reversing time by reprogramming patient-derived stem cells to a pre-malignant state.
“The heterogeneity of MDS makes it a challenging disorder to study,” says Doulatov. “Every patient has a different mutational profile. And within an MDS tumor, there are different clones present, each evolving with a different combination of mutations, pushing the cancer cells through a natural selection process as they constantly fight the immune system and any drugs the patient is given.”
In their investigation, which was funded in part by support from the John H.Tietze Foundation, Doulatov and his team took blood cells from actual MDS patients, reprogrammed them and worked forward again to track the order of the mutations associated with the disease. Along the way, they captured the subclones (the daughter cells of the original cancer cell), tracing the lineage of the disease event by event, like a genealogist assembling a family tree.
Doulatov explains that in addition to understanding the history itself, his lab hopes to uncover the importance of the history. “We don’t know the exact clinical implications, but we do know the more we understand, the more effective we can be at fighting the disease.
Using induced-pluripotent stem cells (iPSC), Doulatov adds, will shed light on the other key questions. “We want to see which events are benign and which are causing damage. The iPSC lines tells us more about the events because we can differentiate in to multiple types of cells and see what paths they take, pathologically.”
In one sample, for example, the researchers observed that the cancer was battering the mitochondria, reducing cell functioning. In other case, the cancer had significantly destabilized the chromosomes.
The findings published in Blood represent proof-of-concept for a novel investigative tool for researchers studying blood diseases. Now, Doulatov has his sights on scaling the method. “We want to super-size the study,” he says. “We want to take hundreds of patients, compile and compare the histories, and look for patterns that could help patients make more informed decisions of treatment plans.” And MDS may not be the only target. Doulatov is also working with Dr. Pamela Becker to extend the reprogramming approach to AML, another blood cancer.
Support for this research comes from the National Heart, Lung, Blood Institute (Blood R00 Transition to Independence Award), the EvansMDS Foundation, and NIH New Innovator Award. Doulatov also received the 2017 Jaconette L. Tietze Young Scientist Research Award.
Blood 2019 :blood.2018884338;