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 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 (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 rare clones and lead to the development of the disease.

From the first phase (hyperdiploidy) to the second (malignant transformation), 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.

Cells with more chromosomes than necessary

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.

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 (before birth) during foetal development, in early hematopoietic progenitor stem cells, which are responsible for generating the various blood cells."

Extra chromosomes and the persistence of rare clones

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.

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 (before birth) during foetal development, in early hematopoietic progenitor stem cells, which are responsible for generating the various blood cells."

Extra chromosomes and the persistence of rare clones

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.

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