Study reveals how hyperdiploidy creates rare pre-leukemic clones in children

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. Now, a study published cell report suggests that this chromosomal instability caused by hyperdiploidy reduces the proliferation of 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, has been led by professors and researchers Oscar Molina and Pablo Menéndez at 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 Namita Thampi, who is also a member of both institutions, is supported by the Spanish Association Against Cancer (AECC).

The study proposes a two-stage model to explain the origin of childhood B-cell acute lymphoblastic leukemia (B-ALL): an initial prenatal stage – hyperdiploidy – and a subsequent postnatal stage – triggered by unknown factors – which is necessary to initiate the malignant transformation of the rare clone and lead to the development of the disease.

From the first stage (hyperdiploidy) to the second (malignant transformation), there can be a time interval of between two and six years, which corresponds to the peak incidence of lymphoblastic leukemia in childhood. It is unclear how these rare clones evolve to cause disease, and understanding this will be important in designing future strategies for childhood leukemia prevention.

cells with more chromosomes than required

This type of lymphoblastic leukemia can develop when a child’s immune system overreacts to a common infection. This response involves the production of large amounts of cytokines and proliferation signals that stimulate bone marrow cells to divide and produce new immune cells.

If a pre-leukemic clone with extra chromosomes is present among these cells, it also receives growth signals and can grow more than normal. Increased cell division further increases the chance of genetic errors. If the clone acquires synergistic mutations, it may eventually develop into leukemia.”

Oscar Molina, member of the UB Department of Physical Sciences

35% to 40% of cases of the disease involve cells with hyperdiploid chromosome counts. In most patients, between 51 and 63 chromosomes are identified, while the normal chromosome number is 46.

“Chromosomal gains in hyperdiploid B-ALL are not random. The most frequently found chromosomes are chromosomes 4, 6, 10, 14, 17, 18, 21, and the X chromosome,” the expert says. “Everything suggests that this excess of chromosomes arises in the uterus “During (before birth) fetal development, early hematopoietic progenitors develop into stem cells, which are responsible for generating various blood cells.”

Persistence of extra chromosomes and rare clones

Studies show that hyperdiploidy causes chromosomal instability, which has effects at various levels. “At the cellular level, it reduces the proliferative ability of cells and delays the differentiation of hematopoietic stem cells, which remain in an undifferentiated state for a longer period of time – a characteristic commonly found in cancer cells,” says Pablo Menendez, a researcher at the Josep Carreras Research Institute.

From a functional point of view, “hyperdiploid cells can persist for some time as rare clones in the bone marrow, but in themselves they are not enough to trigger leukemia,” says Oscar Molina. “These results,” he continues, “help explain what is known as the aneuploidy paradox: chromosomal changes can harm normal cells but, in turn, facilitate tumor progression in some contexts.”

However, these hyperdiploid pre-leukemic clones can persist for years without manifesting clinically. “The factors that trigger the malignant progression of these pre-leukemic clones are not precisely known,” says Menendez.

“The chromosomal gains observed in these cells in animal models are consistent with the chromosomal gains most commonly found in B-ALL patients, which strengthens the clinical relevance of the model and suggests that these gains may contribute to the survival of these preleukemic cells,” explains postdoctoral researcher Namitha Thampi.

Cutting-edge technology for studying lymphoblastic leukemia

Pediatric B-cell ALL is now one of the cancers with the best prognosis in pediatric oncology, with cure rates between 80% and 90% due to combination chemotherapy administered at different stages (induction, consolidation and maintenance), hematopoietic stem cell transplantation (recommended for high-risk patients) and immunotherapy (in cases of recurrence).

One of the most distinctive methodological aspects of this study has been the initial biological sample: human embryonic hematopoietic stem cells, a material that is extremely difficult to obtain and which was provided by the UK Medical Research Council. “This institute has provided us with embryonic material and enabled us to directly study the cells in which the first changes associated with pediatric leukemia arise,” say the authors.

Among other major technologies, single-cell whole-genome sequencing (scWGS) has also been used to analyze the chromosomal content of each individual cell with great accuracy. Xenograft models in immunodeficient mice (NSG) have also been used to study how pre-leukemic clones persist and develop in the bone marrow of the living organism. High-throughput confocal microscopy has enabled 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 amounts of cellular data.