Polycythemia Vera
POLYCYTHEMIA VERA: A RESEARCHER’S VIEW
Stephen T. Oh, M.D., Ph.D.
Assistant Professor, Division of Hematology
Washington University in St. Louis School of Medicine
Q:
What sparked your interest in myeloproliferative neoplasms (MPNs) – specifically, polycythemia vera (PV)?
A:
When I started my post-doctoral fellowship with Dr. Garry Nolan, Professor of Microbiology and Immunology at Stanford, I was already interested in blood cancers. It was a fascinating time: the JAK2 V617F mutation had recently been discovered as a major driver and targeted JAK2 inhibitor therapies were just starting to become available. I also worked with Dr. Jason R. Gotlib, Professorof Medicine (hematology) at Stanford University Medical Center, who is a well-known expert in MPNs, so I was able to be mentored by both.
Q:
When and why did the term “myeloproliferative disorders” change to “myeloproliferative neoplasms”?
A:
The name was formally changed in 2008, soon after the discovery of the JAK2 mutation. The World Health Organization revised the name to signify that PV, as well as essential thrombocythemia and primary myelofibrosis, are indeed blood cancers. It also reflected the evolving understanding of the genetic basis of these conditions, signifying that the presence of the mutation is a diagnosticcriterion for PV, and underscoring that the transition from these conditions to secondary acute myeloid leukemia (sAML) is from one blood cancer to another, not from a pre-cancer to a cancer state.
The World Health Organization revised the name to signify that PV, as well as essential thrombocythemia and primary myelofibrosis, are indeed blood cancers.
Q:
PV’s median age of diagnosis is 61, and transitions from PV to primary myelofibrosis (MF) (bone marrow cancer) and sAML occur with similar frequency for older and younger patients. What percent of those diagnosed with PV are under age 45? Also, do older and younger age cohort patients transition at the same rate or does it differ?
A:
Approximately 15% of PV patients are under age 45. The cumulative incidence is the same for all, but the rate of transition of PV to MF or sAML is longer for younger patients.
Q:
Is the JAK2 mutation germline or somatic? Can it be both?
A:
The mutation is somatic, which means it is acquired at some point in the patient’s lifetime. That being said, it well known that there can be a slight familial disposition. Those with a positive family history of PV are at slightly elevated risk – approximately twofold – of developing PV. However, because PV incidence is relatively low, this doubled risk does not require any special surveillance of family members.
Q:
The JAK2 mutation is present in >95% of patients. Why is your discovery – that other driver mutations are acquired over time – important? Also, why might it explain some of the phenotypic differences between younger and older individuals with PV?
A:
For patients under age 45, only the JAK2 mutation is usually present, whereas older patients will present with at least one additional mutation. This may be due in part to the fact that as people age, clonal hematopoiesis of indeterminate potential (CHIP)can occur, meaning hematopoietic stem cells or other early blood cell progenitors will contribute to the formation of a genetically distinct subpopulation of blood cells. These mutations can become present in acute leukemia as well. Future functional studies on newly discovered mutations may determine if they are driver or passenger mutations, and whether they relate to the development of PV.
Q:
A small percentage of PV patients lack the JAK2 mutation. What, then, is driving their PV?
A:
PV disease, no matter its cause, seems to operate via similar genetic pathways. We don’t know yet what drives JAK2-negative PV, and there is nothing specific to guide their treatment. Interestingly, some do respond to JAK2 inhibitors.
Q:
Are you using CRISPR-Cas9 technology in your PV research?
A:
In my lab, we’re experimenting with using the technology to correct JAK2 and ASXL1 mutations (ASXL1 is one of the mostfrequently mutated genes in malignant myeloid diseases). CRISPR enables precise genetic engineering in human cells, which lets us to study these diseases in ways that were not possible previously. There is obvious interest in the possibility of applying this approach to the clinic. One potential limitation, however, is that for genetically modified (i.e., corrected) clones to take root once transferred back to the patient, bone marrow ablation may be required.
Q:
Could your PV research enable patient treatment to become more personalized and precise?
A:
As our understanding matures of the impact of gene mutations and age differences, we might be able to tailor therapies for specific patients to achieve better outcomes. One avenue we are currently pursuing is improving our understanding of inflammation’s role. PV produces inflammatory cytokines and the inflammatory pathways might steer us to additional targeted therapies.
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Polycythemia Vera
