The Role of PLEKHA8 Gene in T Cell Lymphoblastic Leukemia

Introduction: T-cell acute lymphoblastic lymphoma/leukemia (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. Because of the limitation of specific target treatment, only about 40% T-ALL patients reach the goal of long time survival. To further investigate the pathogenesis and develop the new therapeutic targets of T-ALL, we have developed a Pten tumor suppressor knockout T-ALL mouse model. And in our previous studies, we found PLEKHA8 is highly expressed in Pten conditional knockout mouse T-ALL. PLEKHA8 gene is located at 7p14.3 and its encoding protein regulates the transport of proteins from Golgi complex to cell surface. As a transfer protein in Golgi, PLEKHA8 is important in lipid metabolism and transport. Recent studies showed PLEKHA8 plays a role in glioma and breast tumor in conferring resistance to apoptosis. We hypothesized that PLEKHA8 plays a role in human T-ALL pathogenesis. We investigated if the expression level of PLEKHA8 is aberrant in T-ALL and the effect of altered expression on the apoptosis of human T-ALL cells.

Methods: We conducted bioinformatic analyses on oncomine database. We validated expression levels of PLEKHA8 in human T-ALL cell lines and primary T-ALL samples using western blot and quantitative RT-PCR. PLEKHA8 was knocked down in T-ALL cell lines using a lentivirus based vector with shRNA or CRISPER to assess its effect on cell apoptosis.

Results: The oncomine database showed PLEKHA8 gene was highly expressed in human T-ALL specimens. We confirmed that PLEKHA8 was highly expressed in human T-ALL cell lines in comparison with normal thymic T-cells by Western blot studies. In addition, we confirmed the high expression level of PLEKHA8 in human primary T-ALL cells involving bone marrow by RQ-PCR. T-ALL cells underwent vigorous apoptosis after knockdown PLEKHA8 gene by using shRNA or CRISPER systems.

Conclusion: Our data demonstrated that PLEKHA8 is highly expressed in human T-ALL cell lines and primary T-ALL cells. Decreased expression of PLEKHA8 elicited apoptosis of T-ALL cells. These studies may provide a platform for an effective targeted therapy of T-ALL.