[F31] The Role of the Interferon-alpha Response in Ara-C Resistant Myeloid Leukemia associated with Down syndrome

Description

Project Summary 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 rela Istituzione: WAYNE STATE UNIVERSITY PI: Jenna Thibodeau Progetto: 1F31CA317530-01

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Source: reporter.nih.gov