The many paths of MPNs: New research explores the various genetic paths of patients
Dr. Jyoti Nangalia, Wellcome Sanger Institute
Myeloproliferative neoplasms (MPNs) are rare blood cancers that often unfold slowly. Some people live with stable disease for many years, while others experience progression to myelofibrosis or acute myeloid leukemia (AML). Understanding why these paths differ is a central challenge in MPN research.
A new study, Genomic evolution and natural history of myeloproliferative neoplasms on therapy, led by researchers including Dr. Jyoti Nangalia, takes a long view of this question (Leongamornlert et al., 2026). The project tracks how the genetic makeup of MPN patients change over time and across diagnoses.
A study built on time and depth
Unlike most studies that analyze a single blood sample per patient, this research examined nearly 8,000 blood samples, clinical reports, and treatment histories from the same 30 patients over many years. By sequencing blood samples, the team reconstructed how MPN-related cell populations, known as clones, evolved within each person, including patients who experienced disease progression.
This depth of data allowed the Wellcome Sanger Institute researchers to observe patterns that would otherwise remain hidden, including the genetic events that proceeded AML transformation in 9 patients.
The early days of MPN research, before answers existed
The findings show that MPNs do not follow one uniform course. Instead, the researchers observed patients with several distinct trajectories:
long-term stability, where disease-driving clones changed very little over time
gradual evolution, with new mutations accumulating slowly before clinical progression
sudden transformation, marked by the emergence of genetically distinct leukemia-associated mutations
The 9 MPN patients in the study whose disease developed into AML followed 3 main paths:
loss of both copies of the TP53 gene, which normally helps protect cells from becoming cancerous
a gradual buildup of new genetic changes within existing MPN cell groups
the development of a new, separate group of leukemia cells that is different from the original MPN
In some cases, genetic changes were detectable years before the disease showed signs of worsening in blood counts or other clinical features. This suggests that genomic changes may precede and possibly predict clinical worsening.
Why this matters for patients and clinicians
These insights reinforce the idea that MPN progression is not random. Instead, it reflects underlying genetic changes detectable with monitoring.
The study highlights several important implications:
Repeated genomic testing can reveal early warning signs of progression
Stable disease is represented by real; evident in the long-term stability of clones
Some patients may benefit from closer genetic monitoring, such as those who have lost the TP53 gene
The future of genetic monitoring in MPNs
This and other recent work points toward the growing rationale for genetic testing in treatment decisions (Finazzi et al., 2025; Gagelmann et al., 2025; Heidel et al., 2025; Mansier et al., 2025; Rolles et al., 2026). Today, most patients with polycythemia vera or essential thrombocythemia do not routinely undergo genomic testing, and when testing is used in myelofibrosis, it is often done once. However, this study shows that genetic changes can appear before disease progression.
In the future, more frequent monitoring of a patient’s blood at the genetic level may help doctors spot early signs of disease progression and guide care decisions. As genetic testing becomes increasingly affordable, it could offer a more personalized way to track and manage MPNs.
For patients, caregivers, and clinicians, this research brings us closer to a future where care is guided not only by symptoms, but by an intrinsic metric — genetics — with prognostic abilities.
Proud to support researchers like Dr. Nangalia
This work reflects the value of sustained investment in MPN research. By studying patients over time, MPN scientists hope to uncover how these diseases truly behave, not just at diagnosis, but across years and decades.
Dr. Nangalia is a current member of MPN Research Foundation's Science Advisory Board and was a recipient of the 2019 MPN Challenge award. This funding resulted in groundbreaking research confirming the presence of MPN clonal cell populations decades before disease onset (Williams et al., 2022). MPN Research Foundation is proud to support researchers like Dr. Nangalia, who are conducting long-term research and dedicated to patient education.
You can hear Dr. Jyoti Nangalia explain how genetics, environment, and time shape MPNs and why this research matters in our new You and MPN patient content. https://youtu.be/aMt7QKA9dkQ
Sources:
Finazzi, M. C., Salmoiraghi, S., Valsecchi, F., Pavoni, C., Belotti, C., Grassi, A., Algarotti, A., Lussana, F., Rambaldi, B., Rizzuto, G., Cavallaro, G., Condorelli, A., Bellini, M., Spinelli, O., & Rambaldi, A. (2025). The number of additional high molecular risk mutations predicts outcome after hematopoietic stem cell transplantation in primary and secondary myelofibrosis. Blood Cancer Journal, 15(1), 172. https://doi.org/10.1038/s41408-025-01376-9
Gagelmann, N., Quarder, M., Badbaran, A., Rathje, K., Janson, D., Lück, C., Richter, J., Marquard, F., Oechsler, S., Massoud, R., Klyuchnikov, E., Rudolph, I., Schäfersküpper, M., Niederwieser, C., Heidenreich, S., Berger, C., Fehse, B., Wolschke, C., Ayuk, F., & Kröger, N. (2025). Clearance of Driver Mutations after Transplantation for Myelofibrosis. New England Journal of Medicine, 392(2), 150–160. https://doi.org/10.1056/NEJMoa2408941
Heidel, F. H., De Stefano, V., Zaiss, M., Kisro, J., Gückel, E., Großer, S., Zuurman, M. W., Manz, K., Bryan, K., Afsharinejad, A., Griesshammer, M., & Kiladjian, J.-J. (2025). Prediction of resistance to hydroxyurea therapy in patients with polycythemia vera: A machine learning study (PV-AIM) validated in a prospective interventional phase IV trial (HU-F-AIM). Leukemia, 39(7), 1692–1701. https://doi.org/10.1038/s41375-025-02623-5
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Mansier, O., Lippert, E., Benajiba, L., Ranta, D., Girodon, F., Ianotto, J.-C., Chauveau, A., Roy, L., Boyer, F., Médiavilla, C., Tavitian, S., Divoux, M., Fanet, M., Sloma, I., De Mas, V., Denis, G., Nunes Gomes, C., Calmettes, C., Barraco, F., … French Intergroup of Myeloproliferative Neoplasms (FIM). (2025). A molecular signature predicts hematologic evolution in polycythemia vera patients. Leukemia. https://doi.org/10.1038/s41375-025-02660-0
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Williams, N., Lee, J., Mitchell, E., Moore, L., Baxter, E. J., Hewinson, J., Dawson, K. J., Menzies, A., Godfrey, A. L., Green, A. R., Campbell, P. J., & Nangalia, J. (2022). Life histories of myeloproliferative neoplasms inferred from phylogenies. Nature, 602(7895), 162–168. https://doi.org/10.1038/s41586-021-04312-6