Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels

• Published in: Biochemical and biophysical research communications 2018-01, Vol.495 (3), p.2310-2316
• Main Authors: Miyashita, Kazuya, Kitajima, Kenji, Goyama, Susumu, Kitamura, Toshio, Hara, Takahiko
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; Growth inhibition; HHEX; Humans; Lhx2; LIM Domain Proteins - metabolism; LIM-Homeodomain Proteins - metabolism; Lmo2; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins - metabolism; T-ALL; Transcription Factors - metabolism; Up-Regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.12.135

T cell acute lymphoblastic leukemia (T-ALL) is a malignant cancer with poor prognosis. The transcriptional co-factor LIM domain only 2 (LMO2) and its target gene HHEX are essential for self-renewal of T cell precursors and T-ALL etiology. LMO2 directly associates with LDB1 in a large DNA-containing nuclear complex and controls the transcription of T-ALL-related genes. Recently, we reported that overexpression of the LIM-homeodomain transcription factor, Lhx2, results in liberation of the Lmo2 protein from the Lmo2-Ldb1 complex, followed by ubiquitin proteasome mediated degradation. Here, we found that proliferation of five human T-ALL-derived cell lines, including CCRF-CEM, was significantly suppressed by retroviral overexpression of Lhx2. The majority of Lhx2-transduced CCRF-CEM cells arrested in G0 phase and subsequently underwent apoptosis. Expression of LMO2 protein as well as HHEX, ERG, HES1 and MYC genes was repressed in CCRF-CEM cells by transduction with Lhx2. Lhx2-mediated growth inhibition was partially rescued by simultaneous overexpression of Lmo2; however, both the C-terminal LIM domain and the homeodomain of Lhx2 were required for its growth-suppressive activity. These data indicate that Lhx2 is capable of blocking proliferation of T-ALL-derived cells by both LMO2-dependent and -independent means. We propose Lhx2 as a new molecular tool for anti-T-ALL drug development. •Enforced expression of Lhx2 suppresses the growth of human T-ALL-derived cell lines.•Lhx2 reduces LMO2 protein and downregulates the expression of HHEX, ERG and MYC genes.•Lmo2 overexpression partially rescues the Lhx2-mediated growth inhibition of T-ALL cells.•C-terminal LIM domain and the homeodomain of Lhx2 are required for its growth-suppressive activity.