The musical
Chairs of

How can patients with myeloproliferative neoplasms (MPN) share the same driver mutations but have different disease trajectories?

According to genetic research, the answer lies in dynamic shifts in a person’s genotype that ultimately drive clinical phenotypic changes. “Mutated hematopoietic cells begin to pick up more mutations that give them a clonal selective advantage,” says Dr Michael Savona, Director of Hematologic Malignancies Research and Early Therapy Program at Vanderbilt University Medical Center and founder of CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE), a multidisciplinary group at Vanderbilt studying aging-related clonal hematopoiesis of indeterminate potential (CHIP).

As mutated cells pick up more mutations, the disease progresses, says Dr Savona. “When the mutations lead to a dysregulation in how genes are spliced, or an overproliferation or an epigenetic signal that disrupts how genes are transcribed, it changes the balance of the pro- and anti-inflammatory signaling within the bone marrow.” In turn, when bone marrow gets “out of whack,” says Dr Savona, proteins like danger associated molecular patterns (DAMPs) and toll-like receptors (TLR) change immune signaling in the bone marrow, further propagating an inflammatory signal and increasing the risk of developing more mutants.
A good example of musical chairs played by genes is polycythemia vera (PV). PV is a less severe form of MPN that is characterized by a JAK mutation. When PV transforms into myelofibrosis (post-PVMF), certain non-driver somatic mutations appear, causing genetic changes where phenotype is expressed through cytopenias, leukocytosis, and excessive splenomegaly.

The same is true for patients with primary MF. Nearly all present with at least 1 of 3 common driver mutations—JAK2, CALR, or MPL—but as their disease progresses, other mutations and pathways take the driver’s seat, says Dr Aaron Gerds, assistant professor of hematology and medical oncology at the Cleveland Clinic Taussig Cancer Institute.

“We know that disease can progress and change over time, and that’s often due to other mutations that arrive on the scene in different clones.” He adds, “These second and third mutations are arguably more important than the original ‘driver’ mutation because they are pushing the disease into new phenotypes.”

A good rule of thumb is any time there is a pivot in disease trajectory, order another next generation sequencing (NGS) panel and consult with an MPN subspecialist.

So what does this mean for community hematologists-oncologists? According to Dr Savona, “NGS is standard of care now. These tests can be complex to interpret, so partnering with an MPN specialist can be beneficial to a community hematologist-oncologist, especially when a new mutation may suggest a change in therapeutic approach.” By identifying the ever-changing musical chairs of mutations, researchers are starting to answer questions like: Which mutations signal transformation to leukemia? What are the germline mutations that put one at risk for MF? Which mutations are associated with early disease progression?
“We’re starting to link different genotypes with the actual disease course of an individual,” says Dr Gerds. “It is really exciting and important that it’s becoming therapeutically-based now, and not just about prognosis or something of interest to discuss with a patient.”

Studies that target some of these mutations in MPNs are ongoing, and as treatment options have expanded, community hematologists-oncologists are starting to customize treatment to different phenotypes. “As time goes on,” says Dr Gerds, “understanding these mutations is only going to become more important.”