Poster abstracts
Poster number 63 submitted by Noura Srour
PP2A activation inhibits c-MYC and oxidative phosphorylation in Naive and BTKi Resistant Mantle Cell Lymphoma
Noura Srour, MS (The Ohio State University, Comprehensive Cancer Center, 1Division of Hematology, 2Molecular Cellular and Developmental Biology Graduate Program), Satishkumar Singh1,PhD, Pankajavalli Thirugnanasambantham1, PhD (The Ohio State University, Comprehensive Cancer Center, 1Division of Hematology), Yuanfeng Wang1,2,MS, Dharani Mayilsamy1,PhD, Anuvrat Sircar1,PhD (The Ohio State University, Comprehensive Cancer Center, 1Division of Hematology, 2Molecular Cellular and Developmental Biology Graduate Program), Santhanam Ramasamy1,PhD, Tzyy-Jye Doong,1, Charlene Mao1, Lianbo Yu3,PhD, Yonghua Bao4,PhD, Wancai Yang4, MD, Sam Xing5, Pui-Kai Li5, PhD (The Ohio State University, Comprehensive Cancer Center, 4Division of Clinical and Translational Science, 5Division of Medicinal Chemistry & Pharmacognosy), Lalit Sehgal1,PhD, Natarajan Muthusamy1,DVM,PhD, Neeraj Jain6, PhD (1The Ohio State University, Comprehensive Cancer Center, Division of Hematology; 6CSIR-Central Drug Research Institute, India, Division of Cancer Biology)
Abstract:
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with dismal limited prognosis.1 Treatment relapses are inevitable,1 underscoring the need to identify more MCL targets. Protein phosphatase 2A (PP2A) is a metabolic regulator suppressed in cancer through overexpression of endogenous inhibitors.24 We found that overexpression of the SET nuclear protooncogene (SET), a PP2A catalytic subunit (PP2Ac) inhibitor, in primary MCL is associated with poor prognosis. Hence, we designed and produced XML-3D, a first-in-class small molecule that activates PP2A by inhibiting SET/PP2Ac interactions. We aimed to evaluate XML-3Ds mechanism of action and efficacy in-vitro and in-vivo in MCL. Co-immunoprecipitation and PP2A activity assays confirmed XML-3D-mediated decrease in PP2Ac/SET interactions with PP2A activation. XML-3D induced apoptosis in six independent MCL cell lines and primary MCL samples. MTS assays showed impaired mitochondrial activity, rescued by okadaic acid (p<0.01, n=3), suggesting PP2A-activation dependence. RNA sequencing in MCL cell lines revealed decreased c-MYC and oxidative phosphorylation (OxPhos) targets (p<0.0001, p<0.05, n=3), particularly electron transport chain complex I subunits NDUFA8 and NDUFS6. XML 3D decreased total c-MYC and phospho c-MYC (Ser62), consistent with PP2A mediated c-MYC dephosphorylation and destabilization,3 and reduced OxPhos as confirmed by Western blotting and Seahorse analysis. c-MYC siRNA knockdown decreased NDUFA8 and NDUFS6 protein levels, suggesting c-MYC-dependent expression. MCL resistance to Brutons tyrosine kinase inhibitors (BTKi) is associated with upregulation of c-MYC and OxPhos targets.5 We generated MCL cell lines resistant to the BTKi Zanubrutinib and validated increased OxPhos and c-MYC. XML 3D suppressed OxPhos and induced apoptosis in resistant cells. It significantly slowed tumor progression and improved survival in both nave (n=8, veh, XML-3D) and Zanubrutinib resistant (n=7, veh; n=5, XML-3D) MCL CDX mouse models (p<0.01). Overall, we propose a novel PP2A activating therapeutic that targets c-MYC driven metabolic dependencies in both treatment nave and BTKi resistant MCL, providing mechanistic and preclinical insights for further clinical development.
References:
1.Silkenstedt, E. & Dreyling, M. Treatment of relapsed/refractory MCL. Blood 145, 673682 (2025).
2.Cristbal, I. et al. Overexpression of SET is a recurrent event associated with poor outcome and contributes to protein phosphatase 2A inhibition in acute myeloid leukemia. Haematologica 97, 543550 (2012).
3.Goswami, S. et al. PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia. Blood 139, 13401358 (2022).
4.Liu, Q. et al. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood 111, 275284 (2008).
5.L, Z. et al. Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma. Sci. Transl. Med. 11, (2019).
Keywords: MCL, metabolism, PP2A