GENETIC INSTABILITY AS AN AREA OF POTENTIAL THERAPEUTIC INTERVENTION

Genomic instability is a characteristic feature of myeloid malignancies and the preleukemic syn dromes that predispose to these leukemias. We have accrued evidence in a transgenic mouse model for myeloid disease progression that genomic instability in myeloid malignancies may be driven by a combination of ongoing constitutive DNA damage coupled with altered repair of double strand breaks (DSB) by alternative non homologous end-joining (NHEJ), leading to increased repair infidelity that introduces genomic changes into DNA and drives disease progression. This cycle of DNA damage and misrepair is driven by increased endogenous reactive oxygen species (ROS) production. Treatment of transgenic mice with N-acetyl cysteine results in an up to 30-50% decrease in ROS, DNA damage and concomitant NHEJ misrepair activity. Finally, we find that increased ROS is produced through activation of RAC because specific inhibition of RAC significantly diminishes ROS activity in these mice. RAC is downstream of RAS and is activated by RAS signaling. RAC is also an essential component of NADPH oxidase that produces superoxide radicals. Results with RAC inhibition and antioxidant treatment suggest that combined therapy that may diminish the activities that drive disease progression. Our data serve as a model system to further study the role of activated RAS/MAP kinase pathways and increased ROS in propagating genomic instability and disease progression and could also lead to identification of downstream molecules for therapeutic targeting in an effort to stabilize the genome and halt disease progression in acute myelord leukemia.