The predominant subtype of pediatric malignancy in the blood and bone marrow is B-cell acute lymphoblastic leukemia. A frequent chromosomal anomaly observed in this hematologic neoplasm is the presence of cells exhibiting an excessive number of chromosomes, termed hyperdiploidy. This condition is characterized by inherent chromosomal instability. A recent investigative study, detailed in the publication Cell Reports, elucidates that this chromosomal instability, induced by hyperdiploidy, consequently curtails the proliferative capacity of affected cells, impedes their maturation process, and permits a subset to endure as scarce, long-lived cellular populations within the bone marrow, albeit without initiating overt leukemic development.
This research initiative, which utilized preclinical animal models, was spearheaded by distinguished professors and investigators Òscar Molina and Pablo Menéndez, affiliated with the Faculty of Medicine and Health Sciences at the University of Barcelona and the Josep Carreras Leukemia Research Institute. The published article, with Namitha Thampi, also a member of both aforementioned institutions, serving as the principal author, received crucial financial backing from the Spanish Association Against Cancer (AECC).
The research postulates a sequential, two-phase paradigm to explicate the genesis of pediatric B-cell acute lymphoblastic leukemia (B-ALL). The initial phase involves a prenatal occurrence of hyperdiploidy, followed by a subsequent postnatal stage, purportedly instigated by unidentified environmental or intrinsic factors. This latter stage is imperative for initiating the neoplastic transformation of rare cellular clones, ultimately culminating in the manifestation of the disease.
The temporal interval separating the initial phase (hyperdiploidy) from the secondary phase (neoplastic transformation) might span a period of two to six years, coinciding with the peak incidence observed in childhood lymphoblastic leukemia. The precise mechanisms by which these infrequent clones undergo malignant evolution to precipitate the disease remain enigmatic. Unraveling this intricate process is anticipated to be pivotal in formulating future prophylactic strategies for pediatric leukemia.
Cells Exhibiting Supernumerary Chromosomes
This particular form of lymphoblastic leukemia can arise when a child’s immune system mounts an exaggerated response to a common pathogenic agent. Such an immunological reaction entails the extensive release of cytokines and signals that promote cellular proliferation, thereby stimulating bone marrow cells to undergo division and generate novel immune cells.
Should a pre-leukemic clone characterized by an augmented chromosome count be present among these stimulated cells, it, too, will receive mitogenic signals and consequently proliferate at an accelerated rate compared to normal cells. An increased frequency of cellular division elevates the probability of accumulating further genetic aberrations. If this clone acquires cooperating mutations, it may eventually progress to a leukemic state.”
Òscar Molina, member of the UB’s Department of Physiological Sciences
Between 35% and 40% of all diagnosed cases of this disease involve cells that possess a hyperdiploid chromosome number. In the majority of affected individuals, a chromosome count ranging from 51 to 63 is identified, in stark contrast to the normative complement of 46 chromosomes.
“The chromosomal gains observed in hyperdiploid B-ALL are not random occurrences. The chromosomes most frequently detected in excess are chromosomes 4, 6, 10, 14, 17, 18, 21, and the X chromosome,” the expert pointed out. “All evidence suggests that this surplus of chromosomes originates in utero (prior to birth) during fetal development, specifically within early hematopoietic progenitor stem cells, which are responsible for the generation of all blood cell lineages.”
Additional Chromosomes and the Persistence of Infrequent Clones
The research findings indicate that hyperdiploidy instigates chromosomal instability, which exerts multifaceted effects. “At the cellular level, it diminishes the proliferative potential of cells and retards the differentiation process of hematopoietic stem cells, leading them to remain in an undifferentiated state for extended periods—a hallmark commonly associated with cancerous cells,” stated Pablo Menéndez, a researcher at the Josep Carreras Research Institute.
From a functional standpoint, “hyperdiploid cells can persist for a certain duration as rare clones within the bone marrow, but by themselves, they are insufficient to precipitate leukemia,” elucidated Òscar Molina. “These findings,” he continued, “contribute to an understanding of what is known as the aneuploidy paradox: while chromosomal alterations can be detrimental to normal cells, they can, conversely, facilitate tumor progression in specific contexts.”
Nevertheless, these hyperdiploid pre-leukemic clones possess the capacity to remain dormant for years without exhibiting any clinical manifestations. “The specific factors that instigate the malignant progression of these pre-leukemic clones are not yet precisely identified,” commented Menéndez.
“The chromosomal amplifications observed in these cells within the animal models closely mirror those most frequently encountered in B-ALL patients, thereby bolstering the clinical relevance of the experimental model and suggesting that these gains may indeed contribute to the sustained existence of these preleukemic cells,” explained postdoctoral researcher Namitha Thampi.
Advanced Technological Methodologies for Lymphoblastic Leukemia Investigation
Pediatric B-cell ALL currently holds one of the most favorable prognoses within the field of pediatric oncology, boasting cure rates ranging from 80% to 90%. These successes are attributable to a multifaceted therapeutic approach encompassing combination chemotherapy administered across distinct phases (induction, consolidation, and maintenance), hematopoietic stem cell transplantation (recommended for high-risk individuals), and immunotherapy (utilized in instances of disease relapse).
A particularly distinctive methodological facet of this research endeavor was the utilization of human fetal hematopoietic stem cells as the foundational biological sample. This material is exceptionally challenging to procure, and its availability was facilitated by the UK Medical Research Council. “This esteemed institution furnished us with fetal material, thereby enabling direct investigation of the very cells in which the initial alterations associated with pediatric leukemia originate,” the authors remarked.
Among other cutting-edge techniques employed, single-cell whole-genome sequencing (scWGS) was instrumental in meticulously analyzing the chromosomal complement of each individual cell. Furthermore, xenograft models established in immunodeficient mice (NSG) were leveraged to scrutinize the persistence and evolutionary trajectory of pre-leukemic clones within the bone marrow microenvironment of a living organism. High-throughput confocal microscopy facilitated the automated examination of thousands of cells at remarkable resolution. In this regard, the research team also developed proprietary computational macros to automate the analysis of microscopic imagery and efficiently process extensive volumes of cellular data.
Thampi, N., et al. (2026). 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
