and Akt cooperate to promote leukemogenesis

来自 EBSCO

阅读量：

作者：

R Karnauskas，Q Niu，S Talapatra，DR Plas，ME Greene，JD Crispino，CM Rudin

展开

摘要：

To analyse individual factors that may contribute to leukemic transformation, we have developed a murine model of leukemogenesis based on the early hematopoietic precursor cell FL5.12. FL5.12 cells are interleukin-3 (IL-3) dependent for growth, proliferation, and survival. Relative resistance to cell death following IL-3 withdrawal can be conferred by either overexpression of the Bcl-xapoptotic inhibitor, or constitutive activation of the serine/threonine kinase Akt. The ability of Bcl-xor a constitutively active myristylated Akt to promote leukemic transformation of FL5.12 cells was compared in athymicmice. Bcl-xalone could not promote leukemic transformation, but mice injected with FL5.12 cells overexpressing Bcl-xand a dominant-negative p53 construct developed leukocytosis and blastic infiltration of lymph nodes, spleen, and liver with features of a high-grade lymphoid malignancy. In contrast to the cells injected into these animals, cell lines derived from the mice were able to proliferate in the absence of IL-3, and were found to have constitutively activated Akt. This constitutive activation was associated with a variety of alterations of the signaling pathway regulating Akt activity, including alterations of PTEN mRNA and protein expression. In addition, some of these leukemic clones demonstrated concurrent constitutive upregulation of ERK activity. A constitutively active Akt construct introduced into FL5.12 cells promoted similar clonal expansion, with emergence of clonal IL-3-independent proliferation. Bcl-xand Akt appeared to function cooperatively in this model, enhancing rapid clonal outgrowthrelative to Akt alone. These results implicate activated Akt and growth-factor independence in leukemogenic transformation, and demonstrate the potential foranalysis of genetic determinants of leukemogenesis.

展开

关键词：

Cell Transformation, Neoplastic Leukemia Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 细胞转化, 肿瘤白血病原癌基因蛋白质类原致癌基因蛋白质 c-bcl-2