Dysregulation of c-Myb Pathway by Aberrant Expression of Proto-oncogene MYB Provides the Basis for Malignancy in Adult T-cell Leukemia/lymphoma Cells.
OBJECTIVE
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.


METHODS
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 biologic impacts of abnormal c-Myb overexpression in ATL using overall c-Myb knockdown with shRNA 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-κB signaling. c-Myb-9A induced significantly stronger transactivation of all tested genes and stronger NF-κB 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. Clin Cancer Res; 22(23); 5915-28. ©2016 AACR.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. nakanokz@ims.u-tokyo.ac.jp tnabe@ims.u-tokyo.ac.jp tnabe@marianna-u.ac.jp.
Kazumi
K
Nakano
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Department of Hematology and Oncology, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Kaoru
K
Uchimaru
Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
Atae
A
Utsunomiya
Department of Safety Research on Blood and Biologics, National Institute of Infectious Diseases, Tokyo, Japan.
Kazunari
K
Yamaguchi
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. nakanokz@ims.u-tokyo.ac.jp tnabe@ims.u-tokyo.ac.jp tnabe@marianna-u.ac.jp.|Department of Advanced Medical Innovation, Graduate School of Medicine, St. Marianna University, Kawasaki, Japan.
Toshiki
T
Watanabe
D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D057809:HEK293 Cells; D015490:HTLV-I Infections / Q000235:genetics / Q000821:virology; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000821:virology
C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb