TY - JOUR
T1 - CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia
AU - Cardoso, Bruno A.
AU - Duque, Mafalda
AU - Gírio, Ana
AU - Fragoso, Rita
AU - Oliveira, Mariana L.
AU - Allen, James R.
AU - Martins, Leila R.
AU - Correia, Nádia C.
AU - Silveira, André Bortolini
AU - Veloso, Alexandra
AU - Kimura, Shunsuke
AU - Demoen, Lisa
AU - Matthijssens, Filip
AU - Jeha, Sima
AU - Cheng, Cheng
AU - Pui, Ching Hon
AU - Grosso, Ana R.
AU - Neto, João L.
AU - de Almeida, Sérgio F.
AU - Van Vlieberghe, Pieter
AU - Mullighan, Charles G.
AU - Yunes, J. Andres
AU - Langenau, David M.
AU - Pflumio, Françoise
AU - Barata, João T.
N1 - Publisher Copyright:
©2024 Ferrata Storti Foundation Published under a CC BY-NC license.
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85195225799&partnerID=8YFLogxK
U2 - 10.3324/haematol.2023.282854
DO - 10.3324/haematol.2023.282854
M3 - Article
C2 - 38058200
SN - 0390-6078
VL - 109
SP - 1713
EP - 1714
JO - Haematologica
JF - Haematologica
IS - 6
ER -