Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
AML, Diseases, MDS, Biological Processes, DNA damage, Technology and Procedures, DNA repair, Cell Lineage, Study Population, Myeloid Malignancies
Expression analysis of OASs in AML patients (n=451, Beat AML) showed that OAS1 is upregulated (2-fold) in AML patients compared to normal bone marrow-derived CD34+ hematopoietic stem and progenitor cells (HSPC)(Fig. C). Knockout of OAS1 and OAS2 using Crispr-Cas9 in MDS-L cells (Fig. D), a cell line derived from an MDS patient, confers sensitivity to H2O2-induced DNA damage-mediated cell death; however, OAS3 has no effect. Conversely, ectopic over expression of OAS1 or OAS2 but not OAS3 in HEK293 cells provides protection against H2O2-induced cell death (Fig. E-F). Proteomic analysis of the OAS1 and OAS2 interactome using LCMS/MS suggests that over expression of OAS1 and OAS2 perturbs the differentiation program of HSPCs that may result in neoplastic evolution. Thus, OASs modify PAR chains, promoting speedy DNA repair and cell survival along with the induction of a differentiation block in HSPCs that leads to clonal expansion.
In summary, an overburdened DDR may contribute to AML pathogenesis. Therefore, inhibiting this stimulator of BER/DDR can provide a novel therapeutic avenue in myeloid neoplasms. The current study points to the probable utility of a novel therapeutic approach of targeting OAS in combination with DNA damaging agents to prevent relapse and resistance in the treatment of leukemias.
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Disclosures: Saunthararajah: EpiDestiny: Consultancy, Current equity holder in private company, Patents & Royalties: University of Illinois at Chicago.