Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged protein kinase B (AKT) phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might affect MCL cells in AKT-independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.

1st Department of Medicine Department of Hematology Charles University General Hospital Prague Czech Republic

BIOCEV LF1 Biotechnology and Biomedicine Centre 1st Faculty of Medicine Charles University Prague Czech Republic

Center for Oncocytogenetics Institute of Medical Biochemistry and Laboratory Diagnostics Charles University and General University Hospital Prague Czech Republic

Department of Lymphoma and Myeloma The UT MD Anderson Cancer Center Houston TX

Department of Medical Genetics 3rd Faculty of Medicine Charles University Prague Czech Republic

Institute of Biotechnology BIOCEV Czech Academy of Sciences Prague Czech Republic

Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

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Kumar A, Eyre TA, Lewis KL, Thompson MC, Cheah CY. New directions for mantle cell lymphoma in 2022. Am Soc Clin Oncol Educ Book. 2022;42:1–15. PubMed

Silkenstedt E, Linton K, Dreyling M. Mantle cell lymphoma - advances in molecular biology, prognostication and treatment approaches. Br J Haematol. 2021;195(2):162–173. PubMed

Li JY, Gaillard F, Moreau A, et al. Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization. Am J Pathol. 1999;154(5):1449–1452. PubMed PMC

Eskelund CW, Dimopoulos K, Kolstad A, et al. Detailed long-term follow-up of patients who relapsed after the nordic mantle cell lymphoma trials: MCL2 and MCL3. Hemasphere. 2021;5(1) PubMed PMC

Rudelius M, Pittaluga S, Nishizuka S, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood. 2006;108(5):1668–1676. PubMed PMC

Dal Col J, Zancai P, Terrin L, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood. 2008;111(10):5142–5151. PubMed

Psyrri A, Papageorgiou S, Liakata E, et al. Phosphatidylinositol 3'-kinase catalytic subunit alpha gene amplification contributes to the pathogenesis of mantle cell lymphoma. Clin Cancer Res. 2009;15(18):5724–5732. PubMed

Iyengar S, Clear A, Bödör C, et al. P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood. 2013;121(12):2274–2284. PubMed PMC

Zhao X, Lwin T, Silva A, et al. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun. 2017;8 PubMed PMC

Guan J, Huang D, Yakimchuk K, Okret S. p110α inhibition overcomes stromal cell-mediated ibrutinib resistance in mantle cell lymphoma. Mol Cancer Ther. 2018;17(5):1090–1100. PubMed

Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4(9):1022–1035. PubMed PMC

Karolová J, Kazantsev D, Svatoň M, et al. Sequencing-based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy. Am J Hematol. 2023;98(10):1627–1636. PubMed

Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133(16):1742–1752. PubMed PMC

Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet (London, England) 2016;387(10020):770–778. PubMed

Hess G, Wagner K, Keller U, et al. Final results of a phase I/II trial of the combination bendamustine and rituximab with temsirolimus (BeRT) in relapsed mantle cell lymphoma and follicular lymphoma. Hemasphere. 2020;4(3) PubMed PMC

Till KJ, Abdullah M, Alnassfan T, et al. Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib. Sci Rep. 2023;13(1):3793. PubMed PMC

Jiang VC, Liu Y, Lian J, et al. Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma. J Clin Invest. 2023;133(3) PubMed PMC

Jiang H, Lwin T, Zhao X, et al. Venetoclax as a single agent and in combination with PI3K-MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma. Br J Haematol. 2019;184(2):298–302. PubMed PMC

Stewart CM, Michaud L, Whiting K, et al. Phase I/Ib study of the efficacy and safety of buparlisib and ibrutinib therapy in MCL, FL, and DLBCL with serial cell-free DNA monitoring. Clin Cancer Res. 2022;28(1):45–56. PubMed PMC

Pal D, Vann KR, Joshi S, et al. The BTK/PI3K/BRD4 axis inhibitor SRX3262 overcomes Ibrutinib resistance in mantle cell lymphoma. iScience. 2021;24(9) PubMed PMC

Havranek O, Koehrer S, Comer JM, et al. The B-cell receptor is required for optimal viability, growth, and chemotherapy resistance of diffuse large B-cell lymphoma cell lines of the germinal center B-cell subtype. Blood. 2014;124(21):493. PubMed

Fichtner M, Dreyling M, Binder M, Trepel M. The role of B cell antigen receptors in mantle cell lymphoma. J Hematol Oncol. 2017;10(1):164. PubMed PMC

Henderson J, Havranek O, Ma MCJ, et al. Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry. Cytometry. 2022;101(10):818–834. PubMed

Kapoor I, Bodo J, Hill BT, Almasan A. Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies. Cell Death Dis. 2021;12(11):1061. PubMed PMC

Kapoor I, Li Y, Sharma A, et al. Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies. Cell Death Dis. 2019;10(12):924. PubMed PMC

Kwabi-Addo B, Giri D, Schmidt K, et al. Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci U S A. 2001;98(20):11563–11568. PubMed PMC

Li Y, Podsypanina K, Liu X, et al. Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice. BMC Mol Biol. 2001;2:2. PubMed PMC

Trotman LC, Niki M, Dotan ZA, et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 2003;1(3):E59. PubMed PMC

Wang X, Huang H, Young KH. The PTEN tumor suppressor gene and its role in lymphoma pathogenesis. Aging (Albany NY) 2015;7(12):1032–1049. PubMed PMC

Chang H, Cai Z, Roberts TM. The mechanisms underlying PTEN loss in human tumors suggest potential therapeutic opportunities. Biomolecules. 2019;9(11) PubMed PMC

Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL) Br J Haematol. 2003;121(1):97–100. PubMed

Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A. 1998;95(9):5246–5250. PubMed PMC

Shojaee S, Chan LN, Buchner M, et al. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med. 2016;22(4):379–387. PubMed PMC

Holst F, Werner HMJ, Mjøs S, et al. Amplification associates with aggressive phenotype but not markers of AKT-MTOR signaling in endometrial carcinoma. Clin Cancer Res. 2019;25(1):334–345. PubMed PMC

Vasudevan KM, Barbie DA, Davies MA, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16(1):21–32. PubMed PMC

Erdmann T, Klener P, Lynch JT, et al. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood. 2017;130(3):310–322. PubMed

Bhandari V, Hoey C, Liu LY, et al. Molecular landmarks of tumor hypoxia across cancer types. Nat Genet. 2019;51(2):308–318. PubMed

Kohnoh T, Hashimoto N, Ando A, et al. Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Cancer Cell Int. 2016;16:33. PubMed PMC

Tang M, Bolderson E, O'Byrne KJ, Richard DJ. Tumor hypoxia drives genomic instability. Front Cell Dev Biol. 2021;9 PubMed PMC

Abou Khouzam R, Brodaczewska K, Filipiak A, et al. Tumor hypoxia regulates immune escape/invasion: influence on angiogenesis and potential impact of hypoxic biomarkers on cancer therapies. Front Immunol. 2020;11 PubMed PMC

Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000;14(4):391–396. PubMed PMC

Ricci JE, Chiche J. Metabolic reprogramming of non-Hodgkin's B-cell lymphomas and potential therapeutic strategies. Front Oncol. 2018;8:556. PubMed PMC

Goetzman ES, Prochownik EV. The role for Myc in coordinating glycolysis, oxidative phosphorylation, glutaminolysis, and fatty acid metabolism in normal and neoplastic tissues. Front Endocrinol. 2018;9:129. PubMed PMC

Lien EC, Lyssiotis CA, Cantley LC. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Recent Results Cancer Res. 2016;207:39–72. PubMed

Hu H, Juvekar A, Lyssiotis CA, et al. Phosphoinositide 3-kinase regulates glycolysis through mobilization of aldolase from the actin cytoskeleton. Cell. 2016;164(3):433–446. PubMed PMC

Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64(11):3892–3899. PubMed