title: Role of c-Myb in the survival of pre B-cell acute lymphoblastic leukemia and leukemogenesis.
abstract: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The current treatment protocol for ALL involves an intense chemotherapy regimen yielding cure rates of nearly 80%. However, new therapies need to be designed not only to increase the survival rate but also to combat the risk of severe therapy associated toxicities including secondary malignancies, growth problems, organ damage, and infertility. The c-Myb proto-oncogene is highly expressed in immature hematopoietic cells. In this study, we demonstrate that loss of c-Myb itself decreased the viability of these leukemic cells. Additionally, the inhibition of c-Myb caused a decrease in cell proliferation, significantly increased the number of cells in G(0) /G(1) phase of the cell cycle, increased the sensitivity of pre-B-ALL cells to cytotoxic agents in vitro, and significantly delayed disease onset in a mouse model of leukemia. Furthermore, we demonstrate that Bcl-2 is a target of c-Myb in pre-B-ALL cells. Our results identify c-Myb as a potential therapeutic target in pre-B-ALL and suggest that suppression of c-Myb levels or activity, in combination with currently used therapies and/or dose reduction, may lead to a decrease in toxicity and an increase in patient survival rates. Because c-Myb is aberrantly expressed in several other malignancies, targeting c-Myb will have broad clinical applications.
authors: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Purvaba J
authors: PJ
authors: Sarvaiya
authors: Jason R
authors: JR
authors: Schwartz
authors: Claudia P
authors: CP
authors: Hernandez
authors: Paulo C
authors: PC
authors: Rodriguez
authors: Wayne V
authors: WV
authors: Vedeckis
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004261:DNA Replication / Q000187:drug effects; D004318:Doxycycline / Q000627:therapeutic use; D005260:Female; D055785:Gene Knockdown Techniques; D020570:Genes, myb / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D004318:Doxycycline