CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia.

MTOR protein, human; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, Notch1; T-Cell Acute Lymphocytic Leukemia Protein 1; TAL1 protein, human; TOR Serine-Threonine Kinases; Transcription Factors; CASZ1 protein, human; Animals; Humans; Mice; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Receptor, Notch1/metabolism; Receptor, Notch1/genetics; Transcription Factors/genetics; Transcription Factors/metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction; T-Cell Acute Lymphocytic Leukemia Protein 1/genetics; TOR Serine-Threonine Kinases/metabolism; Zebrafish; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Hematology

Abstract :

[en] CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3K-AKT-mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.

Disciplines :

Hematology

Author, co-author :

Cardoso, Bruno A; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Duque, Mafalda; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Gírio, Ana; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Fragoso, Rita; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Oliveira, Mariana L; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Allen, James R; MGH Pathology and Harvard Medical School, Charlestown MA 02129

Martins, Leila R; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Correia, Nádia C; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon

Silveira, André Bortolini; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP

Bacquelaine Veloso, Alexandra ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie

More authors (15 more)

Language :

English

Title :

CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia.

Publication date :

01 June 2024

Journal title :

Haematologica

ISSN :

0390-6078

eISSN :

1592-8721

Publisher :

Ferrata Storti Foundation, Italy

Volume :

109

Issue :

Pages :

1713 - 1725

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://haematologica.org/article/download/haematol.2023.282854/76382

Funding text :

We thank Dr Thiele for kindly providing the CASZ1 plasmids and Francisco Alexandrino, Hannah Taylor, Ana Sofia Moreira, Danyl Shatalov and Veronika Waas for their technical support. We also thank the mouse, zebrafish and flow cytometry core facilities of Instituto de Medicina Molecular Jo\u00E3o Lobo Antunes for their technical support. This work was supported by the ERC-CoG-648455 and ERC-POC-101069429 grants from the European Research Council, under the European Union\u2019s Horizon 2020 research and innovation program; PTDC/SAU-OBD/69974 grant from Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT), Portugal; and a grant from Children with Leukemia (now Children with Cancer) Charity, UK (to JTB). The work was also supported by EXPL/ MEC-HEM/0571/2021 grant from FCT (to BAC), and grants R01CA211734 and MGH Scholars Award (to DML); and US NCI CA21765 grant to the Cancer center of St. Jude Children\u2019s Research Hospital. ARG and RF were the recipients of FCT Investigator Grants (CEECIND/02699/2017 and CEECIND/03459/2018, respectively). JRA is the recipient of a Howard Hughes Medical Institute Hanna H. Gray Fellowship. ABS and JAY (301596/2017-4) received a fellowship from the Brazilian National Counsel of Technological and Scientific Development (CNPq).This work was supported by the ERC-CoG-648455 and ERC-POC-101069429 grants from the European Research Council, under the European Union\u2019s Horizon 2020 research and innovation program; PTDC/SAU-OBD/69974 grant from Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT), Portugal; and a grant from Children with Leukemia (now Children with Cancer) Charity, UK (to JTB). The work was also supported by EXPL/ MEC-HEM/0571/2021 grant from FCT (to BAC), and grants R01CA211734 and MGH Scholars Award (to DML); and US NCI CA21765 grant to the Cancer center of St. Jude Children\u2019s Research Hospital. ARG and RF were the recipients of FCT Investigator Grants (CEECIND/02699/2017 and CEECIND/03459/2018, respectively). JRA is the recipient of a Howard Hughes Medical Institute Hanna H. Gray Fellowship. ABS and JAY (301596/2017-4) received a fellowship from the Brazilian National Counsel of Technological and Scientific Development (CNPq).

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Bibliography

Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017;129(9):1113-1123.
Belver L, Ferrando A. The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 2016;16(8):494-507.
Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269-271.
Clappier E, Cuccuini W, Kalota A, et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007;110(4):1251-1261.
Gutierrez A, Sanda T, Grebliunaite R, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood. 2009;114(3):647-650.
Homminga I, Pieters R, Langerak AW, et al. Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. Cancer Cell. 2011;19(4):484-497.
Zenatti PP, Ribeiro D, Li W, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43(10):932-939.
Silva A, Yunes JA, Cardoso BA, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118(11):3762-3674.
Mansour MR, Sanda T, Lawton LN, et al. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med. 2013;210(8):1545-1557.
Durinck K, Wallaert A, Van de Walle I, et al. The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia. Haematologica. 2014;99(12):1808-1816.
Correia NC, Fragoso R, Carvalho T, Enguita FJ, Barata JT. MiR-146b negatively regulates migration and delays progression of T-cell acute lymphoblastic leukemia. Sci Rep. 2016;6:31894.
Zhou Y, Han C, Wang E, et al. Posttranslational regulation of the exon skipping machinery controls aberrant splicing in leukemia. Cancer Discov. 2020;10(9):1388-1409.
Silva A, Laranjeira AB, Martins LR, et al. IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Res. 2011;71(14):4780-4789.
Uzan B, Poglio S, Gerby B, et al. Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression. EMBO Mol Med. 2014;6(6):821-834.
Pitt LA, Tikhonova AN, Hu H, et al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. Cancer Cell. 2015;27(6):755-768.
Cardoso BA, de Almeida SF, Laranjeira AB, et al. TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells. Leukemia. 2011;25(10):1578-1586.
Peirs S, Matthijssens F, Goossens S, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124(25):3738-3747.
Maude SL, Dolai S, Delgado-Martin C, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125(11):1759-1767.
De Smedt R, Morscio J, Reunes L, et al. Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. Blood. 2020;135(19):1685-1695.
Liu Z, Yang X, Tan F, Cullion K, Thiele CJ. Molecular cloning and characterization of human Castor, a novel human gene upregulated during cell differentiation. Biochem Biophys Res Commun. 2006;344(3):834-844.
Charpentier MS, Christine KS, Amin NM, et al. CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway. Dev Cell. 2013;25(2):132-143.
Christine KS, Conlon FL. Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline. Dev Cell. 2008;14(4):616-623.
Dorr KM, Amin NM, Kuchenbrod LM, et al. Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development. Development. 2015;142(11):2037-2047.
Huang RT, Xue S, Wang J, et al. CASZ1 loss-of-function mutation associated with congenital heart disease. Gene. 2016;595(1):62-68.
Sojka S, Amin NM, Gibbs D, Christine KS, Charpentier MS, Conlon FL. Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity. Development. 2014;141(15):3040-3049.
Mellerick DM, Kassis JA, Zhang SD, Odenwald WF. castor encodes a novel zinc finger protein required for the development of a subset of CNS neurons in Drosophila. Neuron. 1992;9(5):789-803.
Isshiki T, Pearson B, Holbrook S, Doe CQ. Drosophila neuroblasts sequentially express transcription factors which specify the temporal identity of their neuronal progeny. Cell. 2001;106(4):511-521.
Liu Z, Yang X, Li Z, et al. CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression. Cell Death Differ. 2011;18(7):1174-1183.
Liu Z, Naranjo A, Thiele CJ. CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth. PLoS One. 2011;6(4):e18557.
Wang JL, Yang MY, Xiao S, Sun B, Li YM, Yang LY. Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling. J Exp Clin Cancer Res. 2018;37(1):45.
Liu Z, Zhang X, Lei H, et al. CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG. Nat Commun. 2020;11(1):911.
Wu YY, Chang CL, Chuang YJ, et al. CASZ1 is a novel promoter of metastasis in ovarian cancer. Am J Cancer Res. 2016;6(6):1253-1270.
Bagger FO, Sasivarevic D, Sohi SH, et al. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis. Nucleic Acids Res. 2016;44(D1):D917-D924.
Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, et al. ETV6 mutations in early immature human T cell leukemias. J Exp Med. 2011;208(13):2571-2579.
Borssen M, Palmqvist L, Karrman K, et al. Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia. PLoS One. 2013;8(6):e65373.
Staal FJ, de Ridder D, Szczepanski T, et al. Genome-wide expression analysis of paired diagnosis-relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia. 2010;24(3):491-499.
Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med. 2004;200(5):659-669.
Seront E, Rottey S, Filleul B, et al. Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma. BJU Int. 2016;118(3):408-415.
Blackburn JS, Liu S, Raiser DM, et al. Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia. 2012;26(9):2069-2078.
Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia. 2007;21(3):462-471.
Bernard M, Delabesse E, Novault S, Hermine O, Macintyre EA. Antiapoptotic effect of ectopic TAL1/SCL expression in a human leukemic T-cell line. Cancer Res. 1998;58(12):2680-2687.
Correia NC, Arcangeli ML, Pflumio F, Barata JT. Stem cell leukemia: how a TALented actor can go awry on the hematopoietic stage. Leukemia. 2016;30(10):1968-1978.
Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1(1):75-87.
O’Neil J, Shank J, Cusson N, Murre C, Kelliher M. TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell. 2004;5(6):587-596.
Kelliher MA, Seldin DC, Leder P. Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha. Embo J. 1996;15(19):5160-5166.
Sanda T, Lawton LN, Barrasa MI, et al. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):209-221.
Palomero T, Odom DT, O’Neil J, et al. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia. Blood. 2006;108(3):986-992.
Kusy S, Gerby B, Goardon N, et al. NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia. J Exp Med. 2010;207(10):2141-2156.
Herblot S, Steff AM, Hugo P, Aplan PD, Hoang T. SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression. Nat Immunol. 2000;1(2):138-144.
Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13(10):1203-1210.