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

Award Number: F31CA317530
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2027
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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The Role of the Interferon-alpha Response in Ara-C Resistant Myeloid Leukemia associated with Down syndrome - 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 relapsed ML-DS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Research Manpower	000	1	9/3/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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

Award Number: F31CA317530

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2027

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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