Abstract 3076: A niche driven mechanism determines response to ATRA and a mutation-independent therapeutic approach forMDS and AML

Abstract Myeloid cancers remain resistant to standard of care (SOC) and targeted therapies. An oncogenic signal from the niche, constitutive activation of β-catenin/JAG1 signaling in osteoblastic cells (osb-β-catenin), leads to myelodysplasia (MDS) and acute myeloid leukemia (AML) and occurs in ∼40% of MDS and AML patients and patients with del(5q)-associated myeloid malignancies. We show that its levels increase with disease severity and correlate with MDS to AML transformation and a worse overall survival. Searching for regimens that block osb-β-catenin activity we identified all-trans-retinoic acid (ATRA), a regimen with disparate results in MDS and AML. By analyzing publicly available RNA-seq data and bone marrow biopsies collected from 14 ATRA-treated patients from four different study sites we found a strong association between inhibition of osb-β-catenin activity and/or Notch signaling in AML cells with ATRA, leading to AML improvement. An overall response rate of 100% was reached in patients with active baseline osb-β-catenin, as compared to 22% among patients without this pathway active. Responsiveness was observed across patients with diverse cytogenetic and mutational profiles belonging even to adverse risk groups. Improvement occurred despite a diverse ATRA dosing schedule in combination with other therapeutic agents (AZA, VEN, VPA). Indeed, whereas there was no association between response and the degree of global DNA hypomethylation or histone acetylation among patients treated in combination with AZA/VPA, we observed high association of treatment response with baseline osb-β-catenin activity (p=0.021). Moreover, first-line AZA/VEN treatment of an AML patient resulted in relapse and CR was reached only upon ATRA addition to AZA/VEN backbone. Supporting this conclusion, treatment with ATRA monotherapy of an MDS patient with high levels of active osb-β-catenin improved disease status and was associated with complete inhibition of osb-β-catenin activity and a parallel decrease in Notch signaling in the patient’s MDS cells. The patient remained transfusion independent for at least 9 years. Mechanistically, ATRA-mediated inhibition of osb-β-catenin activity suppressed cell growth and survival and promoted differentiation of MDS/AML cells solely from patients with active osb-β-catenin without toxicity in healthy cells. Confirming findings in patient samples, ATRA administration in leukemic mice suppressed osb-β-catenin signaling thus improving disease outcome and prolonging survival by at least six-fold with no evidence of relapse and a superior safety profile to SOC. These results suggest that responsiveness to ATRA may be predicted by measuring activation of β-catenin in osteoblasts. Thus, repurposing ATRA use for the treatment of this specific group of patients may significantly improve disease outcome. Citation Format: Ioanna Mosialou, Abdullah M. Ali, Alvaro Cuesta-Dominguez, Brian Chernak, Marta Galan-Diez, Mael Heiblig, Ellin Berman, Joseph G. Jurcic, Steven Kornblau, Guiliermo-Garcia Manero, Azra Raza, Stavroula Kousteni. A niche driven mechanism determines response to ATRA and a mutation-independent therapeutic approach forMDS and AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3076.