A new study has identified specific subpopulations of preleukemic stem cells (PSC) linked to acute lymphoblastic leukemia (ALL) development, shedding light on the early stages of this common childhood cancer.
Preleukemic fusion genes (PFG), which arise prenatally, were analyzed to determine their immunophenotype and potential for malignant transformation. Researchers sorted and investigated hematopoietic stem and progenitor cells (HSPC) from umbilical cord blood (UCB) of pediatric ALL patients and healthy controls. Utilizing fluorescent in situ hybridization (FISH), they detected diagnostically-relevant gene rearrangements associated with ALL.
The results identified TEL/AML1+ PSC subpopulations as CD34+ CD38+ and CD34+ CD38− cells, which exhibited increased genetic instability, indicating their possible role as targets for malignant transformation. This research not only confirms the prenatal origin of these genetic mutations but also suggests the potential for early screening of ALL.
This study, published on March 15, 2025, involved samples from four pediatric ALL patients, who ranged in age at diagnosis from 45 to 120 months, and compared their immunophenotype and genetic stability against those of ten healthy children.
Patient-specific insights revealed varying levels of PFG across different samples. For example, one patient's UCB revealed 1.5% TEL/AML1+ cells within progenitors, whereas another had only 0.1% positivity among HSC/MPP. This variability highlights interindividual differences which might influence disease progression and therapeutic responses.
The findings indicate significant genetic instability linked with ALL-associated genes such as TEL, AML1, BCR, ABL, and MLL across the analyzed subpopulations. These genetic changes were significantly more pronounced compared to those observed in healthy controls, emphasizing the inherent risks of ALL development from these precursor cells.
The innovative methodologies employed allowed for direct genetic analysis, providing reliable evidence of PFG existence many years before clinical diagnosis of ALL. The dual-fusion and break-apart probe analysis used demonstrate not only the presence of PFG but also additional rearrangements and mutational burdens associated with leukemia.
Overall, the study suggests HSPC subpopulations harboring preleukemic genetic changes could provide potential targets for immunotherapy and early intervention strategies, which could lower relapse rates and improve outcomes for patients diagnosed with ALL.
By identifying these genetic markers linked to ALL, researchers assert the importance of monitoring umbilical cord blood for early signs of leukemic transformation. This could open new avenues for risk assessment and screening strategies aimed at reducing the incidence of ALL among children.
The findings from this study remain fundamental as they not only improve our knowledge of ALL's pathogenesis but also mark significant progress toward developing preventive measures against this cancer.
Currently, there is only limited information on the exact cell of origin for various ALL subtypes, which complicates the early detection and treatment of this prevalent form of childhood leukemia. The innovative study offers fresh insights and emphasizes high genetic instability within these preleukemic states as precursors to leukemia development.
Continued investigation of these PSC and their immunophenotypes is necessary to provide more precise screening methods and therapeutic approaches, potentially reshaping our strategies for combating pediatric acute lymphoblastic leukemia.