Dysregulation of c-Myb pathway in ATL malignancy

Purpose: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive human T-cell malignancy induced by human T-lymphotrophic virus-1 (HTLV-1) infection. The genetic alterations in infected cells that lead to transformation have not been completely elucidated, thus hindering the identification of effective therapeutic targets for ATL. Here, we present the first assessment of MYB proto-oncogene dysregulation in ATL and an exploration of its role in the onset of ATL. Experimental Design: We investigated the expression patterns of MYB splicing variants in ATL. The molecular characteristics of the c-Myb-9A isoform, which was overexpressed in ATL cells, were examined using chromatin immunoprecipitation and promoter assays. We further examined the biological impacts of abnormal c-Myb overexpression in ATL using overall c-Myb knockdown with small hairpin RNA or c-Myb-9A knockdown with morpholino oligomers. Results: Both total c-Myb and c-Myb-9A, which exhibited strong transforming activity, were overexpressed in ATL cells in a leukemogenesis- and progression-dependent manner. Knockdown of either total c-Myb or c-Myb-9A induced ATL cell death. c-Myb transactivates nine genes that encode essential regulators of cell proliferation and NF-B signaling. c-Myb-9A induced significantly stronger transactivation of all tested genes and stronger NF-B activation compared with wild-type c-Myb. Conclusions: Our data demonstrate that c-Myb pathway overactivation caused by unbalanced c-Myb-9A overexpression is associated with disorders in cellular homeostasis and consequently, accelerated transformation, cell proliferation, and malignancy in ATL cells. These data support the notion of the c-Myb pathway as a promising new therapeutic target for ATL.

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