B-cell acute lymphoblastic leukemia is the most common form of childhood cancer. In this type of cancer, which affects blood cells, one of the most common abnormalities is the presence of cells with an excess of chromosomes (hyperdiploidy), a condition that leads to chromosomal instability.
B-cell acute lymphoblastic leukemia is the most common form of childhood cancer. In this type of cancer, which affects blood cells, one of the most common abnormalities is the presence of cells with an excess of chromosomes , a condition that leads to chromosomal instability.
Now, a study published in Cell Reports reveals that this chromosomal instability caused by hyperdiploidy reduces the proliferation of the affected cells, delays their differentiation and allows some to persist as rare, long-lived clones in the bone marrow, but without triggering leukemia.The study, conducted using animal models, is led by professors and researchers Òscar Molina and Pablo Menéndez from the Faculty of Medicine and Health Sciences of the University of Barcelona and the Josep Carreras leukemia Research Institute. The paper, whose lead author is Namitha Thampi, also a member of both institutions, is supported by the Spanish Association Against Cancer . The study proposes a two-stage model to explain the origin of childhood B-cell acute lymphoblastic leukemia : an initial prenatal stage — hyperdiploidy — and a subsequent postnatal stage — triggered by unknown factors — which is necessary to initiate the malignant transformation of rare clones and lead to the development of the disease. From the first phase to the second , there may be a time window of between two and six years, which corresponds to the peak incidence of childhood lymphoblastic leukemia. It remains unclear how these rare clones evolve to cause the disease, and understanding this will be key to designing future strategies for the prevention of childhood leukemia.This type of lymphoblastic leukemia can develop when a child's immune system responds excessively to a common infection. This response involves the production of large amounts of cytokines and proliferation signals that stimulate the bone marrow cells to divide and produce new immune cells. If the pre-leukemic clone with extra chromosomes is present among these cells, it also receives growth signals and can proliferate more than normal. Increased cell division raises the likelihood of further genetic errors. If the clone acquires synergistic mutations, it may eventually develop into leukemia."Between 35% and 40% of cases of the disease involve cells with a hyperdiploid chromosome count. In most patients, between 51 and 63 chromosomes are identified, whereas the normal chromosome count is 46. "Chromosomal gains in hyperdiploid B-ALL are not random. The chromosomes most frequently found in excess are chromosomes 4, 6, 10, 14, 17, 18, 21 and the X chromosome," notes the expert. "Everything suggests that this excess of chromosomes arises in utero during foetal development, in early hematopoietic progenitor stem cells, which are responsible for generating the various blood cells."The study reveals that hyperdiploidy causes chromosomal instability, which has effects at various levels. "At the cellular level, it reduces the proliferative capacity of cells and delays the differentiation of hematopoietic stem cells, which remain in an undifferentiated state for longer — a characteristic commonly found in cancer cells," says Pablo Menéndez, a researcher at the Josep Carreras Research Institute.From a functional perspective, "hyperdiploid cells can persist for some time as rare clones in the bone marrow, but on their own they are not sufficient to trigger leukemia," says Òscar Molina. "These results," he continues, "help to explain what is known as the aneuploidy paradox: chromosomal changes can harm normal cells, but, in turn, facilitate tumor progression in certain contexts." However, these hyperdiploid pre-leukemic clones can also persist for years without manifesting clinically. "The factors that trigger the malignant progression of these pre-leukemic clones are not precisely known," notes Menéndez. "The chromosomal gains observed in these cells in animal models correspond to those most commonly found in B-ALL patients, which reinforces the clinical relevance of the model and suggests that these gains may contribute to the persistence of these preleukaemic cells," explains postdoctoral researcher Namitha Thampi.Paediatric B-cell ALL is now one of the cancers with the best prognosis in paediatric oncology, with cure rates of between 80% and 90% thanks to combination chemotherapy administered in different phases , hematopoietic stem cell transplantation and immunotherapy . One of the most distinctive methodological aspects of this study has been the initial biological sample: human fetal hematopoietic stem cells, a material that is extremely difficult to obtain and which was provided by the UK Medical Research Council. "This institution has provided us with foetal material and enabled us to study directly the cells in which the first alterations associated with paediatric leukemia originate," the authors note. Among other leading techniques, single-cell whole-genome sequencing has also been used to analyse the chromosomal content of each individual cell with great precision. Xenograft models in immunodeficient mice have also been used to study how pre-leukemic clones persist and evolve in the bone marrow of a living organism. High-throughput confocal microscopy has enabled the automated examination of thousands of cells at high resolution. In this regard, the team has also developed its own computer macros to automate the analysis of microscopic images and process large volumes of cellular data.Thampi, N., et al. . Hyperdiploidy impairs fetal hematopoietic progenitor fitness and differentiation enabling persistence of rare preleukemic aneuploid clones. Cell Reports. DOI: 10.1016/j.celrep.2026.117173. https://www.sciencedirect.com/science/article/pii/S2211124726002512
Blood Bone Bone Marrow Cell Chromosome Malignant Medicine Proliferation Research Stem Cells
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