MPN Progression Research Network (PRN)
The PRN Summit
The entire MPN Progression Research Network meets approximately once a year, to report on research, discuss findings, and set future goals.
The 4th MPN Progression Research Summit was held in January 2024.
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Working collaboratively to understand MPN disease progression
The Progression Research Network (PRN) is a coalition of MPN physician-scientists and advocates working collaboratively to improve long-term outcomes for patients through research on the prevention and treatment of disease progression. Initiated by MPN Research Foundation in September of 2020, the PRN grew from an unmet need brought to the forefront by patients wanting to better understand how progression would affect their MPN journey.
We do not yet fully understand why a patient progresses along the spectrum from lower to higher risk MPNs — or why one does not progress — especially given the fact that patient cases and physician treatment plans are rarely alike. If we did, these critical insights about progression would help personalize treatment plans for clinicians and alleviate uncertainty for patients.
The next frontier
MPN Research Foundation believes that disease progression is the next frontier for MPN research. We used our convening power to assemble the PRN, which brings researchers, industry, and MPN advocates together to further the mission of improving patient outcomes through research into the prevention and treatment of disease progression.
Progression Research Network objectives
The Progression Research Network aims to better define progression and identify biomarkers that may predict disease progression. Ultimately we aim to define new clinical endpoints to target with new treatments.
With more understanding and treatments to address slowing, stopping, or reversing disease progression, we can improve care guidelines and personalized treatment approaches.
The sharing of data and resources is a guiding principle of the PRN, and many members are working in close collaboration on several ongoing research projects funded in part by the MPN Research Foundation.
Progression research projects
Identifying and Validating Actionable Biomarkers in MPN Progression
Researchers: Ann Mullally, MD, Brigham and Women’s Hospital
Rebekka Schneider, MD, PhD, University Hospital RWTH
Research summary
The project is focused on two potential biomarkers of MPN progression, SLAMF7 in a type of white blood cells called monocytes, and CXCL4 in blood and bone marrow cells. Monocytes were found to be increased in numbers in MPN patients with essential thrombocythemia and polycythemia vera and might be responsible in progression to MF. These monocytes exhibit high expression of the signaling molecule called SLAMF7 which can be targeted with a drug elotuzumab. Dr. Mullally’s group proposes that SLAMF7 and a cell surface marker protein CD14 could potentially be used as biomarkers of progression to MF. Dr. Schneider is investigating CXCL4 as a potential biomarker for initiation of bone marrow fibrosis and progression.
Previous studies demonstrated higher gene expression of CXCL4 in bone marrow from both mice and patients, and the absence of CXCL4 enhanced the MPN phenotype in mice, including reduction in the number of monocytes and fibrosis. Bone marrow samples from more than 250 patients are being analyzed. CXCL4 protein analysis (ELISA) has been performed on ~400 patients including 56 controls and shows progressively higher levels of CXCL4 during fibrotic progression.
The two research groups are collaborating on integrating the SLAMF7 and CXCL4 data to understand how the blood forming cells and the surrounding bone marrow microenvironmental cells “talk to each other” to advance the disease. This will enable the identification of novel and targetable biomarkers at various stages of progression and therefore potentially allow physicians to intervene early on.
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- Dr. Schneider’s previous research indicated higher gene expression of CXCL4 gene in bone marrow samples from mice and human patients. Of note, the absence of CXCL4 rectified the MPN traits in mice.
- CXCL4 is also being evaluated as a potential blood biomarker of fibrotic progression in MPN patients.
- The integrations of results from these studies could provide pivotal insights that might steer improvements in future diagnostic and therapeutic strategies for MPNs.
Evaluation of TP53 Pathway Regulators in Progression of Myeloproliferative Neoplasms
Researchers: Bridget Marcellino, MD, PhD, Icahn School of Medicine, Mt. Sinai
Ron Hoffman, MD, Icahn School of Medicine, Mt. Sinai
Research summary
If we imagine our genes as a set of instructions for how our body works, sometimes there are typos (mutations or deletions) or extra words (increased expression), which can make things go wrong, causing diseases to progress. Dr. Marcellino and her team are studying a specific cellular stress response network in the body which is associated with cancer, the TP53 pathway, to understand its role in the advancement of MPNs. TP53 is a tumor suppressor gene that helps repair damaged DNA of diseased cells, or eliminate the cells, but this pathway seems to be compromised in MPNs.
This study is shedding light on how this important pathway — responsible for suppressing tumor cells and protecting us — can go awry. It is important to investigate the potential mechanisms that might be responsible for the dysfunction of this pathway to further understand how it facilitates the progression of MPN disease.
Importantly, a large, multi-institutional database is being developed for this study, housing clinical and molecular information from more than 2,000 patients.
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- Using blood-forming stem cells from MPN patients, the research team aims to validate if the genes MDM2, MDM4, and PPM1D can serve as biomarkers (indicators) for TP53 pathway dysfunction, which could provide insights to medical practitioners about potential disease progression in specific patients.
- Such a large database is essential to analyzing enough patients to make concrete conclusions.
- By providing a clearer understanding of how MPNs might progress, studies such as this can help in the development of better treatments and disease management strategies.
Interrogating the Spatial Architecture of MPN Disease Progression
Researcher: Stephen Oh, MD, PhD, Washington University in St. Louis
Research summary
In this investigation of MPN patient bone marrow, researchers are taking highly detailed images of marrow samples, identifying the spatial arrangement of various cells in it, and analyzing what is happening in each individual cell to better understand how MPNs progress. This insight will provide a deeper comprehension of MPN’s underlying mechanisms, potentially leading to the development of more effective therapies.
The team created a special mix of markers to identify different types of cells in samples from MPN patients across disease progression. The markers also identified signals these cells send out, to understand each cellular “player” and their specific roles.
Imaging mass cytometry, a powerful analytical technique, was used to look at individual cells and allowed a view into which cells might be causing an MPN to get worse. Certain white blood cells called CD14 positive monocytes were observed to release signals (TNF and other cytokines) that could be problematic. In patients with MF, other unique characteristics were found in the bone marrow, including protein markers that hint at disease progression. They were also able to see that as MF worsens and potentially changes to AML, certain markers in the cells increase, which might be a sign of the disease progressing.
The study’s methodologies — including the image analysis and use of single-cell technology — are set to pinpoint abnormal cell populations that could be driving MPN progression.
Collaboration has been key, with additional MPN patient samples and analytical support shared from other institutions in addition to data analysis support. As more patient samples are analyzed, the researchers are studying if these findings hold true for a larger group.
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- The researchers developed and fine-tuned multiplex imaging
antibody panels and image analysis system to identify various
blood-forming stem and progenitor (descendent) cell populations
that can be identified by presence of crucial cytokine and signaling
biomarkers on them (specifically TNF, IL-6, pS6, and pCREB). - These cells could be contributing to or potentially driving MPN
progression, especially those that show NFkB hyperactivation, which
is not affected by ruxolitinib. - MF patient bone marrow analysis revealed collagen fibers, pCREB
and pS6 protein markers, blood and platelet forming cells in
abundance. Patients advancing to leukemia displayed pCREB, pERK
and pSTAT5 proteins in their blood forming cells, suggesting that
they might be instrumental in progression.
MPN Stem and Progenitor Cell Clonal Fitness as Predictors of Progression
Researchers: Joseph Scandura, MD, PhD, Weill Cornell Medicine
Ron Hoffman, MD, Icahn School of Medicine, Mt. Sinai
Research summary
MPN stem cells are the root cause of problems experienced by patients with these diseases. They are so powerful that even a single mutant MPN stem cell is thought to start what can be a decades-long process that eventually leads to an MPN diagnosis and, potentially, to progression of that MPN to more aggressive diseases. This single MPN stem cell can do this because it outcompetes normal blood-forming elements to take over blood cell production. The focus of this project is to determine if directly measuring the competitive success of MPN cells — termed “MPN fitness” — can be used as a much needed surrogate for the long-term outcomes of patients, such as progression.
One reason it is not known how to prevent progression is because clinical trials do not use progression in the evaluation of treatment effectiveness (called an endpoint). This is because measuring progression would require infeasibly long times and prohibitive expense to evaluate since the studies could potentially run for many years.
Disease progression is likely the clinical summary of many biological events that increase the competitive advantages of MPN stem cells over time. This is associated with changes in the bone marrow where the stem cells live, the accumulation of new mutations in the stem cells, and the effects of inflammation.
The hypothesis proposed here is that knowing MPN fitness may allow one to measure core MPN biology that is driving the risks of MPN progression. This was demonstrated by isolating stem cells and their different types of progeny (offspring) from patient blood and measuring the proportion of MPN and normal cells.
A strong correlation was found between MPN fitness level and event-free survival. Patients whose MPN fitness dropped while undergoing therapy generally fared better. In contrast, those with rising MPN fitness during treatment displayed more aggressive disease traits and faced more MPNassociated events, such as thrombosis (blood clots) and disease progression. The team is also working to develop methods to analyze MPN fitness in a “onetube” system that can be performed in a clinical pathology laboratory.
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- Next steps include use of MPN fitness patterns to monitor patients in clinical trials as a possible surrogate endpoint for patient outcomes.
- Using MPN fitness as a tool would allow studies of progression to be completed in a feasible time period.
- This work introduces a new method to continuously and personally track a patient’s disease risk, including risk of progression, and potentially tailor treatment strategies accordingly
Targeting the HMGA1 Epigenome in MPN Progression
Researchers: Linda Resar, MD, The Johns Hopkins University School of Medicine
Alison Moliterno, MD, The Johns Hopkins University School of Medicine
Leslie Cope, PhD, The Johns Hopkins University School of Medicine
Research summary
Operating much like an on and off switch, epigenetic regulators are naturally occurring proteins that control expression of genes involved in cell growth and behavior. Dr. Resar’s group discovered HMGA1 as an epigenetic “key” required to “unlock” the genome and activate gene networks required for chronic MPN to progress to myelofibrosis or leukemia. In this study, her team is investigating how HMGA1 becomes activated in MPN and what happens after HMGA1 is activated, in order to develop new therapies to prevent MPN progression.
They found that HMGA1 is activated by the JAK2 mutation and, in turn, HMGA1 flips on multiple gene pathways that foster MPN progression, including bone marrow fibrosis. In some cases, HMGA1 unlocks gene networks that disrupt cell growth and behavior, leading to leukemia. More recent work also suggests that HMGA1 turns off genes that allow the immune system to attack mutant MPN cells.
They are now searching for pathways that could be disrupted with therapy to prevent fibrosis and leukemia development while stimulating the immune system to attack the mutant MPN cells.
This extensive study — including collaborations with five institutions and seven researchers — advances our understanding of HMGA1’s intricate role in MPN progression, providing solid groundwork for developing targeted therapies to inhibit it.
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- Preliminary research also indicates HMGA1 is linked to excessive platelet production and may contribute to blood clotting complications seen in MPN patients.
- In experimental models, reducing HMGA1 levels in cells from MPN patients not only stops the growth and spread of the disease, but also makes these cells more responsive to the JAK inhibitor ruxolitinib.
- The continuation of this research is crucial to unlocking new and more effective treatment avenues for MPN patients.
Characterizing the Role of Inherited Genetic Variation in MPN Disease Progression
Researcher: Vijay Sankaran, MD, PhD, Boston Children’s Hospital
Research summary
Given that secondary acute myeloid leukemia is more aggressive than primary AML, there is a clear need to further understand the inherited genetic features that could lead to more responsive prevention of MPN progression to AML. The studies are utilizing very large populations, first to examine the overlap between germline genetic variants that predispose one to the development of MPN or AML, and second to look at the genetic variants that could make individuals with MPN more susceptible to transformation to AML.
The team’s most recent results indicate that inherited genetic variants that increase the risk for acquiring MPNs also contribute to the risk for progression. This offers valuable insights that could shape future preventative measures and targeted treatments for affected individuals.
The significance of these considerably expanded population studies cannot be overstated as larger pools from the general population are necessary to better understand the occurrence of MPN mutations and variants in genes that may be associated with the disease and its progression. Robust databases such as the UK Biobank, Finngen, 23andMe, BioVU, Wellcome Trust, and All of Us amounted to ~7,000 cases and ~1.1 million controls..
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- One key challenge noted is the frequently late diagnosis and data base coding of an MPN, leading to inaccuracies regarding “time to AML” and survival analyses.
- The large genetic pool from multiple international databases enabled the identification of a number of new genetic loci (locations within a gene or another DNA segment) which may be associated with MPNs.
- According to this study, 7% of MPN patients progress to AML in ~5 years of diagnosis, leading to decreased survival.
