The Savona Lab
Dr Savona’s lab at Vanderbilt focuses on the study of clonal hematopoiesis to accelerate treatments for myeloid diseases, like MF.
Just two decades ago, customized therapy for patients with myelofibrosis seemed like science fiction, says Dr Savona. But gains in research and technology, as well as the canonical discovery of the JAK mutation, have pulled back the curtain on a new set of discoveries in precision medicine. This milieu is where Dr Savona and his team dedicate their work—sifting through the stacks of various genetic code, searching for different mutations and their frequency in the bloodstream, and identifying which subtle signs are most important in contributing to the patients’ condition.
Mutations in myelofibrosis can change as often as acts on open mic night.
Alex Silver, MD/PhD student working under Dr Savona (left).
The lab team is working to answer fundamental questions about the biology of myeloid disease, how hematopoietic cells evolve under different pressures, which biomarkers are critical to pathogenesis and disease progression, and how all this information translates from bench to bedside.
“We’re getting better at understanding an individual patient’s prognosis, and how their trajectory is going to look, much of which comes from recognizing specific mutations and other ways in which their cells are unique,” says Alex Silver, an MD/PhD student working under Dr Savona’s tutelage at the Savona Lab at Vanderbilt. “We are now entering into an age of genetic medicine, where we’ll be able to target specific genetic changes that are harming the patient to try to mitigate those deleterious effects.”
Some key genetic players have already been identified.
The ASXL1 mutation in myelofibrosis signifies a higher risk of transformation to acute leukemia. When Dr Savona sees this on the results of a patient’s next generation sequencing (NGS) panel, he says he might speak more to the benefits of pursuing a stem cell transplant with his patient because the benefits might outweigh the risks in this setting.
Other genetic players in MF include splicing mutations (SRSF2, U2AF1, SF3B1, and ZRSR2), which are present in ~50% of MF patients and are associated with cytopenias. When these appear, says Dr Savona, he may be less worried about acute leukemia and more focused on the likelihood of transfusion dependence and how that informs treatment selection.
Activating mutations have also been explored. Well named, these mutations make myelofibrosis more active—hematopoietic cells become more apt to acquire new mutations and spin into more proliferative disease. Also in the mix, of course, are driver mutations, such as the familiar JAK2V617F, as well as epigenetic mutations, like ASXL1 mentioned above. In other words, mutations in myelofibrosis can change as much as acts on open mic night.
Donovan, a research assistant working in the Savona Lab (above).
Dr Savona’s CHIVE project brings together biologists, geneticists, and AI data scientists.
At Vanderbilt, Dr Savona and team have access to a biobank of samples and anonymized medical health records from patient volunteers. With these materials, Dr Savona’s lab assesses patients’ DNA to see how their phenotypes match their genotypes. What makes Vanderbilt’s database unique is they have been collecting DNA for a couple of decades, says Dr Savona. “In some cases, we have DNA that is 20 years old, and if we’re lucky, we have that same patient’s DNA from 10 years ago, 5 years ago, and 2 years ago, and we can see changes in their blood.”
In 2020, Dr Savona started another collaborative project known as CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE). Through CHIVE, experts across disciplines at Vanderbilt, including molecular biology, genetics, and data science, work together to better understand age-related clonal hematopoiesis and its contribution to myeloid disease. “What we are doing at CHIVE is prospectively studying specific genetic changes over time and trying to pinpoint which ones are the most risky,” says Dr Savona.
This is important because clonal hematopoiesis, an age-related phenomenon, does not guarantee evolution to myeloid disease, he says. “The key is understanding why 10% of 70-year-olds have clonal hematopoiesis, but not all 10% get MDS or myelofibrosis. How does it go from point A to point B? That’s the challenge.” Dr Savona adds, “We are starting to formulate some ideas about that.”
In addition, Dr Savona’s research is helping to elucidate the molecular epidemiology of myeloid disease, how often different genes appear, and how they function and interact with each other. “That’s a whole new ball of wax,” says Dr Savona. “I think the generation after me is going to be dealing with patients and molecular biology and a manipulation of genetic abnormalities in a way that we can barely fathom right now.”