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
  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation, Leukemic
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases*/metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/pathology
  • Proto-Oncogene Proteins c-akt*/metabolism
  • Receptor, Notch1/genetics
  • Receptor, Notch1/metabolism
  • Signal Transduction*
  • T-Cell Acute Lymphocytic Leukemia Protein 1*/genetics
  • T-Cell Acute Lymphocytic Leukemia Protein 1*/metabolism
  • TOR Serine-Threonine Kinases*/metabolism
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Zebrafish*
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping