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Abstract
Disease progression in myeloid malignancies results from the accumulation of "mutations"
in genes that control cellular growth and differentiation. Many types of genetic alterations
have been identified in myeloid diseases. However, the mechanism(s) by which these
cells acquire genetic alterations or "Genomic instability", is less well understood.
Increasing evidence suggests that the genetic changes in myeloid malignancies lead
to increased production of endogenous sources of DNA damage, such as, reactive oxygen
species (ROS). The fusion gene BCR-ABL in chronic myeloid leukemia (CML), FLT3/ITD
in acute myeloid leukemia (AML), and RAS mutations in myelodysplastic syndromes (MDS)/myeloproliferative
diseases (MPD) result in ROS production. Increased ROS can drive a cycle of genomic
instability leading to DNA double strand breaks (DSBs) and altered repair that can
lead to acquisition of genomic changes. Evidence is coming to light that defects in
a main repair pathway for DSBs, non-homologous end-joining (NHEJ), lead to up-regulation
of alternative or "back-up" repair that can create chromosomal deletions and translocations.
This article will review evidence for activation of RAS/PI3K/STAT pathways, that lead
to increased ROS, DNA damage and defective repair in myeloid diseases, a mechanism
for acquisition of additional mutations that can drive disease progression.