Trouble in the neighborhood: How one type of chromosome abnormality is more common than previously thought

  • Jill Hoffmann | January 27, 2025

    Trouble in the neighborhood: How one type of chromosome abnormality is more common than previously thought

    A recent study by Dr. Vesna Najfeld and her team brings fresh insights into myelofibrosis (MF), a type of myeloproliferative neoplasm (MPN). Their work highlights the importance of closely tracking genetic changes over time and suggests that changes around a gene called HMGA2 could help predict cancer progression. 

    What is HMGA2 and why is it important? 

    The HMGA2 gene is best known for its role during embryonic development, where its protein helps regulate the activity of genes that control cell-cycle progression, senescence, and proliferation. Later in adult blood-forming cells, the HMGA2 gene is typically inactive. When it’s switched back “on” in adults, it can lead to problems. Overactive HMGA2 expression has been linked to cancers, including worse outcomes in a type of blood cancer called acute myeloid leukemia (AML). 

    Building on previous research, scientist Dr. Vesna Najfeld and colleagues at the Icahn School of Medicine at Mount Sinai, New York used advanced tools to map chromosome changes surrounding the HMGA2 gene to uncover its relationship to blood cancer such as MPNs and disease progression. To accomplish this, they looked at the major abnormalities that can pop up in HMGA2’s chromosome neighborhood. 

    What does “12q14.3” mean? 

    If DNA is like a street map, “12q14.3” is a precise address. It pinpoints a location on chromosome 12, specifically on its long arm (“q”). Chromosomes have identifiable patterns of light and dark bands when stained and viewed under a microscope. In this address, “14” refers to a band, and “.3” specifies a smaller subsection within that band. 

    This region likely plays a role in keeping the HMGA2 gene inactive during adulthood. When deletions occur in this area, research suggests that HMGA2 protein production goes unchecked. 

    Dr. Vesna Najfeld and her team analyzed the circulating blood cells from 741 MPN patients and compared their 12q chromosomes to those of healthy, normal donors (ND). They discovered that chromosome deletions around the HMGA2 gene were more common in MF patients than scientists previously thought. Specifically, novel deletions in the 12q14.3 region occurred in 11.7% of MF patients. These abnormal chromosome changes were not seen in patients with other MPN subtypes, such as essential thrombocythemia (ET) or polycythemia vera (PV). Even in MF patients without 12q14.3 abnormalities, “virtually all MF patients overexpressed HMGA2 compared to ND.” 

    Why testing for genetic changes over time matters 

    Traditionally, doctors test a patient’s genetic profile during diagnosis and sometimes when symptoms worsen, or the disease becomes more aggressive. But there’s more to a patient’s genetic journey than one or two isolated data points.  

    While not the first to track the genetic changes of patients over time, this study stands out for highlighting the importance of longitudinal genetic testing in understanding myelofibrosis as well as popularizing an approach that could meaningfully improve disease progression knowledge. 

    By testing and re-testing study participants, Dr. Najfeld and her team demonstrated the power of viewing patients not as having static diagnoses but experiencing dynamic genetic changes which emerge along their disease timeline.

    This innovative approach challenges researchers to reconsider how genetic studies are conducted and inspires clinicians to look beyond single test results when making treatment decisions.  

    “To better understand and pre-empt disease evolution, a patient’s genomic information should ideally be assessed more proactively than reactively,” Dr. Najfeld emphasized. “Such information could affect treatment decisions, transplant consideration, or counseling before the clinical condition deteriorates.” 

    By including this data, the study demonstrated that HMGA2-related genetic changes don’t occur all at once but develop as the disease progresses. Patients with 12q14.3 abnormalities were more likely to experience an aggressive clinical course, including advancing to the blast phase of the disease at a much higher rate than patients with other genetic profiles. 

    What could this mean for care? 

    Patients often wonder how research like this will impact their treatment. While the study underscores the potential of HMGA2 testing, Dr. Najfeld cautioned that it’s still early days. “Physicians and insurance companies likely want to see the correlations we observed, especially the one with disease progression, confirmed in a larger cohort of patients before advocating for, committing to, and reimbursing for routine testing of a patient’s HMGA2 expression status,” explains Dr. Najfeld. 

    Still, the study’s findings suggest that more comprehensive genetic testing could provide vital clues about what a patient should expect. For instance, the study found that patients with 12q14.3 changes were more likely to have larger spleens and higher levels of immature blood cells (blasts). 

    Interestingly, HMGA2 abnormalities were more frequently observed in patients with CALR mutations compared to those with JAK2 mutations. This finding could help explain why CALR-mutated patients may face a higher risk of disease progression. 

    Looking to the future 

    Although more research is needed, this study points to a future where doctors use HMGA2 and other genetic markers to personalize treatment for MF patients. By monitoring these markers over time, clinicians could anticipate changes and adjust care before symptoms worsen. 

    Dr. Najfeld’s work highlights how genetic testing could change the way we manage MPNs, offering patients and doctors new tools to stay one step ahead of the disease. It’s a hopeful step toward a future where care is tailored to each patient’s unique genetic profile. 

    Disease progression is a critical focus of the MPN Research Foundation, and we’re actively supporting researchers in uncovering the driving factors. Genetic data, like the insights explored by Dr. Najfeld and her colleagues, offer invaluable clues but remain limited. One of our top priorities is advancing research in this area to fill those gaps. To learn more about how we’re addressing the challenges of disease progression, check out our recent white paper discussing a path forward. 

    Sources:

    Handa, S., Schaniel, C., Tripodi, J., Ahire, D., Mia, M. B., Klingborg, S., Tremblay, D., Marcellino, B. K., Hoffman, R., & Najfeld, V. (2024). HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis. Leukemia, 1–12. https://doi.org/10.1038/s41375-024-02496-0 

    Certain medicines listed may not be approved by the US Food and Drug Administration (FDA) for myelofibrosis but are recommended by the National Comprehensive Cancer Network (NCCN). MPN Research Foundation works with NCCN on the creation and updating of its MPN Patient Guidelines.

    The Sweet Dilemma: Balancing Sugar Intake and Cancer Risk This Halloween 

    Understanding Fibrocytes: Key players in myelofibrosis