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.

CASZ1是一种保守的转录因子，参与神经发育、血管组装与心脏形态发生。CASZ1在癌症中的作用可能因组织类型而异，既可抑制（如神经母细胞瘤）也可促进（如卵巢癌）肿瘤发生，而其在血液系统恶性肿瘤中的功能尚不明确。本研究发现，诊断时的T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）细胞高表达CASZ1b，且主要T细胞癌基因TAL1是CASZ1的直接正调控因子。体外实验表明，CASZ1b过表达可转化Ba/F3细胞；体内实验则以PI3K依赖的方式驱动肿瘤发生。值得注意的是，CASZ1b可与ICN1协同，通过提升白血病细胞的增殖活性与存活能力，在斑马鱼模型中促进T-ALL发生。此外，CASZ1b过表达可使人T-ALL细胞抵抗血清剥夺与化疗药物处理。与之相符的是，高CASZ1表达水平与更短的复发时间及更差的总生存期显著相关。本研究还发现，T-ALL患者体内CASZ1b的表达与PI3K-Akt-mTOR信号通路的激活呈正相关；且与Ba/F3细胞类似，在T-ALL细胞中过表达CASZ1b可激活PI3K通路。上述发现具有重要的治疗指导意义：过表达CASZ1b的T-ALL细胞对PI3K药物抑制具有敏感性。综上，本研究证实CASZ1b是TAL1的靶基因，可促进T-ALL发生并介导化疗耐药。PI3K-Akt-mTOR信号通路抑制剂或许可成为CASZ1阳性复发型T-ALL患者的潜在治疗手段。