DNA damage accumulation and repair defects in FLT3-ITD acute myeloid leukemia: Implications for clonal evolution and...

Acute myeloid leukemia is a group of hematological diseases that have a high mortality rate. During the development of this pathology, hematopoietic cells acquire chromosomal rearrangements and multiple genetic mutations, including FLT3-ITD. FLT3-ITD is a marker associated with a poor clinical prognosis and involves the activation of pathways such as PI3K/AKT, MAPK/ERK, and JAK/STAT that favor the survival and proliferation of leukemic cells. In addition, FLT3-ITD leads to overproduction of reactive oxygen species and defective DNA damage repair, both implicated in the appearance of new mutations and leukemic clones. Thus, the purpose of this review is to illustrate the molecular mechanisms through which FLT3-ITD generates genetic instability and how it facilitates clonal evolution with the generation of more resistant and aggressive cells. Likewise, this article discusses the feasibility of combined therapies with FLT3 inhibitors and inhibitors of DNA repair pathways.