The role of the interferon-alpha response in ARA-c… (F31CA317530) – Project Grant to Wayne State University

Abstract: Although most patients with myeloid leukemia associated with down syndrome (ML-DS) are cured with cytarabine (ARA-c)-based chemotherapy, relapsed/refractory cases have extremely poor clinical outcomes with no clinical biomarkers or salvage therapies in place. These clinical findings highlight the urgent need for a better understanding of ARA-c-resistance mechanisms in ML-DS and the development of effective therapies for this vulnerable group of patients. Our lab has identified sterile alpha motif and HD-domain containing protein 1 (SAMHD1), a deoxynucleotide triphosphate (dntp) hydrolase, as a major driver of ARA-c inactivation in ML-DS by converting ARA-CTP, the active ARA-c metabolite, back into its prodrug form (ARA-c). Immunoblot analysis demonstrates that SAMHD1 is substantially upregulated in ARA-c-resistant ML-DS cells (CMY) compared to ARA-c-sensitive ML-DS cells (CMK). Genetic knockdown of SAMHD1 in CMY cells shows a strong concentration-dependent resensitization to ARA-c with a consistent increase of ARA-CTP, demonstrating SAMHD1 to be a promising therapeutic target, yet there is little known about the mechanism of SAMHD1 upregulation. Our previous proteomic and pathway enrichment analyses identified the interferon alpha (IFN-α) response as the most significantly enriched pathway in ARA-c-resistant ML-DS cells compared to ARA-c-sensitive counterparts. We also observed strong upregulation of IFN-related DNA damage resistant signature (irds) genes in ARA-c-resistant ML-DS cells. Irds genes are canonically enriched in chemotherapy-, immunotherapy-, or radiotherapy-resistant cancers and are transcribed because of chronic IFN-α stimulation. My preliminary data show that ARA-c-sensitive CMK cells display an inducible type i IFN response which elevates SAMHD1 and increases resistance to ARA-c. IFN signaling is thought to confer resistance through transcriptional reprogramming and persistent activation of interferon-stimulated genes (isgs). However, the exact consequences of this modulated signaling pathway in ML-DS remain to be discovered. I hypothesize that aberrant IFN-α/JAK/stat signaling sustains elevated expression of irds genes and SAMHD1 and by directly inhibiting the IFN-α/JAK/stat pathway, ARA-c efficacy can be restored in relapsed ML-DS patients. This project will define a previously unrecognized mechanism of ARA-c resistance in ML-DS driven by chronic IFN-α signaling and sustained SAMHD1 expression. By receiving training from experts in omics-based studies, INF signaling and clinical research, i will gain a comprehensive scientific understanding, learn new research techniques, and build professional networking skills. I will also collaborate with my CO-sponsor, DR. Jeffrey taub, to understand the clinical needs and challenges of this patient population. By uncovering the biology underlying resistance-associated gene regulation, this work will lay the foundation for future therapeutic strategies for patients with relapsed ML-DS.

The role of the interferon-alpha response in ARA-c resistant myeloid leukemia associated with down syndrome

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