Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, associate clinical laboratory director, Omniseq/Labcorp, Buffalo, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Age-dependent evolution pattern in MDS arising from GATA2 deficiency
October 2025—GATA2 deficiency is a rare inherited condition that disrupts the normal development of blood and immune cells. People born with this genetic disorder may experience low blood counts, frequent infections, or such problems as lymphedema and hearing loss. The most serious long-term risk is development of myelodysplastic syndrome (MDS), a bone marrow disorder that can progress to leukemia. The authors conducted a large study in which they followed 218 people with confirmed GATA2 mutations to understand when and how MDS develops. In this cohort, symptoms of GATA2 deficiency were present in 205 of the participants, of whom 187 (91.2 percent) had MDS. The median age at the time of MDS diagnosis was 12.9 years. Only 12 (7.2 percent) patients were younger than six years old at diagnosis, and the youngest was 1.7 years old. MDS was rarely seen in very young children and was not found in infants. After preschool age, the risk of MDS rose quickly—almost half of this cohort had the disorder by 12 years old and nearly all had been affected by late adolescence. The type of GATA2 genetic alteration had a major impact on disease course. Mutations that disabled the gene, or null variants, were linked to earlier onset of MDS and more frequent additional symptoms, including lymphedema and hearing loss. Changes in intron 4, the regulatory domain of the gene, were associated with a much milder course of the disorder. Many study participants with intron 4 variants stayed healthy well into adulthood and did not exhibit symptoms seen in those with other variants. Those with missense variants demonstrated an intermediate pattern of symptoms. The authors also evaluated genetic changes in bone marrow for the study. The most common abnormality was loss of an entire copy of chromosome 7, called monosomy 7, which was seen in more than half of those tested. This change often occurred alongside mutations in such genes as SETBP1, ASXL1, and EZH2. SETBP1 mutations, in particular, almost always appeared with monosomy 7 and signaled a more aggressive form of MDS. These findings have clear implications for care. Routine blood counts may be enough to monitor the health of preschool-aged children with GATA2 deficiency since the risk of MDS is low at this young age. From school age onward, however, the sharp rise in MDS risk suggests a need for more frequent checks and, in some cases, evaluation of bone marrow, even if blood counts appear normal. Knowing the type of GATA2 mutation helps determine how closely someone should be watched. High-risk genetic changes in bone marrow, such as monosomy 7 or SETBP1 mutations, should lead clinicians to consider earlier treatment, including bone marrow transplant. By considering age, mutation type, and bone marrow findings, clinicians can better predict who is at greater risk of MDS and take action before the disorder progresses. This approach offers the best chance of preventing serious complications and improving long-term outcomes for those living with GATA2 deficiency.
Kotmayer L, Kozyra E, Kang G, et al. Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency. Blood Cancer J. 2025. doi.org/10.1038/s41408-025-01309-6
Correspondence: Dr. Marcin W. Wlodarski at [email protected]
Fusion-derived neoantigens as a trigger of endogenous T cells in pediatric acute leukemias
Fusion genes are a well-recognized driver in pediatric acute leukemias, producing chimeric proteins that can generate unique fusion-derived neoantigens. These antigens are restricted to the leukemic clone, making them attractive targets for immunotherapy. While molecular diagnosis of fusions is routine, less is known about how often the endogenous T-cell repertoire detects and responds to these fusion-derived neoantigens (fNA) in children. The authors conducted a study to determine whether fNA trigger immune response in pediatric patients. For the study, they analyzed 34 pediatric patients, who had acute lymphoblastic leukemia (ALL, n =15), acute myeloid leukemia (AML, n =15), or mixed phenotype acute leukemia (MPAL, n = 4). Bone marrow and peripheral blood samples were dominated by leukemic blasts (median, 92 percent), and the median frequency of lymphocytes was 3.5 percent. The authors used a rapid expansion protocol to overcome low lymphocyte proportion. The expanded T cells were cocultured with their autologous leukemic blasts, resulting in a significant increase in CD8+ and CD4+ T-cell reactivity in 97 percent (33 of 34) of samples. The reactive T cells were further sorted and enriched for CD8+ and CD4+ cells for T-cell receptor sequencing. The authors identified reactive T-cell clones, which were not among the largest clones in the sorted T-cell populations but were reactive to leukemic blasts and fusion neoantigens. The pattern was heterogeneous—patients with the same fusion often had different neoantigen peptides recognized by their immune systems, indicating variable antigen processing and presentation. Of note, these clones were only identified when the patient was not receiving therapy, such as during diagnosis or relapse. Responses were more common in remission than at the time of diagnosis, suggesting that therapy-related reduction in tumor burden and immune suppression may enhance reactivity. The authors also identified the T-cell receptors that recognize fusion-derived neoantigens and control leukemia progression in vivo. However, the T-cell response in AML and MPAL required interferon gamma (IFN-γ), while ALL blasts were eliminated by reactive T cells without IFN-γ treatment. These findings demonstrate that a substantial proportion of pediatric patients naturally mount T-cell responses against fusion-specific neoantigens and these responses may influence the ability to control disease. This supports the rationale for immunotherapeutic strategies, such as using peptide vaccines or T-cell receptor-engineered T cells customized to the patient’s fusion and immunogenic epitope profile.
Tirtakusuma R, Ghonim MA, Schattgen S, et al. Endogenous T cell responses to fusion-derived neoantigens in pediatric acute leukemias. Leukemia. doi.org/10.1038/s41375-025-02710-7
Correspondence: Dr. Paul G. Thomas at [email protected]