Childhood B-Cell Preleukemia Mouse Modeling

Abstract

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.

Keywords: childhood leukemia; genetic predisposition; leukemia; mouse modeling; preleukemic cells.

Figure 1

Childhood B-ALL development in genetically predisposed carriers. A “two-hit” model has been proposed for most cases of B-ALL. B-ALL development requires an initiating mutation acquired prenatally (first hit), which leads to the preleukemic cell generation, as well as a second postnatal mutation (second hit). Genetic susceptibility to childhood leukemia (first hit) could be due to inherited genetics (A) or due to prenatal somatic aberrations such as chromosomal aberrations (B). In both cases, the genetic alteration gives rise to preleukemic cells that are susceptible to transformation. In this model, the second hit is triggered by postnatal environmental factors. Recent pieces of evidence have shown that those environmental factors, such as infection, can promote immune stress in the preleukemic cells leading to the development of overt leukemia. It is of note that the preleukemic cells could be around in healthy individuals who will never develop leukemia, as the incidence of childhood B-ALL is much less frequent than the frequency of preleukemic healthy carriers.