PUBLICATION

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

Authors
Cardoso, B.A., Duque, M., Gírio, A., Fragoso, R., Oliveira, M.L., Allen, J.R., Martins, L.R., Correia, N.C., Silveira, A.B., Veloso, A., Kimura, S., Demoen, L., Matthijssens, F., Jeha, S., Cheng, C., Pui, C.H., Grosso, A.R., Neto, J.L., De Almeida, S.F., Van Vlieberghe, P., Mullighan, C.G., Yunes, J.A., Langenau, D.M., Pflumio, F., Barata, J.T.
ID
ZDB-PUB-231207-14
Date
2023
Source
Haematologica   109(6): 1713-1725 (Journal)
Registered Authors
Langenau, David
Keywords
none
MeSH Terms
  • TOR Serine-Threonine Kinases*/metabolism
  • Proto-Oncogene Proteins c-akt*/metabolism
  • Mice
  • Phosphatidylinositol 3-Kinases*/metabolism
  • Receptor, Notch1/genetics
  • Receptor, Notch1/metabolism
  • T-Cell Acute Lymphocytic Leukemia Protein 1*/genetics
  • T-Cell Acute Lymphocytic Leukemia Protein 1*/metabolism
  • Humans
  • Animals
  • Zebrafish*
  • Signal Transduction*
  • Cell Line, Tumor
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/pathology
  • Gene Expression Regulation, Leukemic
(all 19)
PubMed
38058200 Full text @ Haematologica
Abstract
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 PI3KAKT- 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.
Genes / Markers
Figures
No images available
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zdf12TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    No data available
    Fish
    No data available
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
    Show
    Mapping
    No data available
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    Citation
    Cardoso, B.A., Duque, M., Gírio, A., Fragoso, R., Oliveira, M.L., Allen, J.R., Martins, L.R., Correia, N.C., Silveira, A.B., Veloso, A., Kimura, S., Demoen, L., Matthijssens, F., Jeha, S., Cheng, C., Pui, C.H., Grosso, A.R., Neto, J.L., De Almeida, S.F., Van Vlieberghe, P., Mullighan, C.G., Yunes, J.A., Langenau, D.M., Pflumio, F., Barata, J.T. (2023) CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia. Haematologica. 109(6):1713-1725.