From the Clinic to the Lab: Dr. Mullally takes on big questions.
by Marina Sampanes Peed
The energy Dr. Ann Mullally brings to her work is apparent as soon as she starts speaking. She talks quickly but clearly is not a fast-talker. I could tell that she began her hematology work as a physician because she brought a practical sensibility to her presentation at the CR&T 8th International Patient Symposium on Myeloproliferative Neoplasms.
Dr. Mullally began her studies in medicine at University College Dublin in Ireland. She then moved to Baltimore for her medical Residency at Johns Hopkins Hospital in Internal Medicine. From there, she moved to Boston for a Hematology Oncology Fellowship at Dana-Farber Cancer Institute which is affiliated with Harvard Medical School.
Her clinical experience with MPN patients stirred her curiosity and desire to help move science further down the road to a solid understanding of these complex diseases. With that, Dr. Mullally became a physician/researcher, straddling the distinct worlds of patient care and intense research.
In 2013, Dr. Mullally’s research talent attracted enough funding to start her own independent research lab at Brigham and Women’s Hospital, Department of Hematology, with Harvard Medical School. She assembled a talented team of five people who bring unique strengths to her translational hematology research lab. They use a variety of state of the art methods (single-cell mass cytometry, quantitative proteomics, and next generation gene sequencing). They also use in vivo shRNA screening (used to examine genes that regulate cells in mice).
As patients, we often ask Who, What, When, Where, Why, and How questions about these complex MPNs. Every question seems to lead to several more. Dr. Mullally is clear about the big questions she seeks to answer in her lab: what happens in the microenvironment that supports the mutated stem cells to survive and what are the best ways to block that activity?
She points out that mutations occur in everyone throughout their lives, and most don’t result in disease. I was surprised to learn that the JAK2 mutation is detectable in some people with “healthy” blood (they don’t have a MPN). This was determined incidentally in a study for diabetes in 2014. So why does the mutation result in PV or MF for some and not others?
Much of Dr. Mullally’s current work is to determine what factors are at work in some MPN patients that cause Myelofibrosis to occur. “We think Myelofibrosis happens because JAK2 and CALR produce inflammation proteins (also called cytokines) which cause fibrosis in the bone marrow. There are many proteins and the question is which inflammatory proteins might be important to this activity?” Exploring this question requires a lot of mice.
Dr. Mullally and her team study cytokine levels in mice and people with Myelofibrosis. She says the cytokines are higher when MF is present in humans and mice compared to their healthy counterparts. One key cytokine that promotes fibrosis, TGF-B, is in the bone and other organs. Because cytokines effect more than one cell system, a lot of modeling and testing much occur before conclusions are made.
With the support of a 2014 MPN Challenge Grant from the MPN Research Foundation, Dr. Mullally is also working to identify the role of the gene, CHD4, in the development of fibrosis in the bone marrow.
Dr. Mullally also aims to understand which of the growth factors help the mutated hematapoietic stem cell (HSC) survive. Then test drugs to block the activity of these growth factors, thus killing the mutated HSC. This approach will lead to more successful treatments for MPN and leukemia, resulting in a higher cure rate for patients.
All this research takes focus, attention to detail, and the ability to publish the work and findings for peer review. And of course, continue to write grants to keep the research going. Stay tuned for new knowledge that will emerge from Dr. Mullally’s lab.
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