CASZ1 activates PI3K-Akt-mTOR signaling and acts as an oncogene in T-cell Acute Lymphoblastic Leukemia

CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. The impact of CASZ1 in cancer may vary depending on the tissue, either suppressing (e.g. neuroblastoma) or promoting (ovarian cancer) tumor development. The role of CASZ1 in hematological cancers is unknown. Here, we show that diagnostic T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress CASZ1b and that TAL1, a major T-cell oncogene, is a direct a positive regulator of CASZ1. Overexpression of CASZ1b transforms Ba/F3 cells in vitro, and drives tumor development in vivo, in a PI3K-dependent manner. Notably, CASZ1b cooperates with ICN1 to promote T-ALL in zebrafish, by increasing proliferation and viability of leukemia cells. Moreover, overexpression of CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. In agreement, high CASZ1 levels associate with shorter time to relapse and decreased overall survival. Finally, we found that CASZ1b expression in T-ALL patients correlates with PI3K-Akt-mTOR signaling pathway activation, and, similar to Ba/F3 cells, CAZ1b overexpression in T-ALL cells leads to PI3K pathway activation. These findings have therapeutic implications, since treatment with T-ALL cells overexpressing CASZ1b are sensitive to PI3K pharmacological inhibition. Taken together, our studies indicate that CASZ1b is a TAL1 target that promotes T-ALL development and resistance to chemotherapy. Inhibitors of PI3K-Akt-mTOR signaling pathway may be attractive therapeutic tools for relapsed CASZ1-positive T-ALL patients.