title: Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling.
abstract: SPA-1 (signal-induced proliferation associated gene-1) functions as a suppressor of myeloid leukemia by negatively regulating Rap1 signaling in hematopoietic progenitor cells (HPCs). Herein, we showed that transplantation of HPCs expressing farnesylated C3G (C3G-F), a Rap1 guanine nucleotide exchange factor, resulted in a marked expansion of thymocytes bearing unique phenotypes (CD4/CD8 double positive [DP] CD3(-) TCRbeta(-)) in irradiated recipients. SPA-1(-/-) HPCs expressing C3G-F caused a more extensive expansion of DP thymocytes, resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL) with massive invasion of clonal T-cell blasts into vital organs. The C3G-F(+) blastic thymocytes exhibited constitutive Rap1 activation and markedly enhanced expression of Notch1, 3 as well as the target genes, Hes1, pTalpha, and c-Myc. All the T-ALL cell lines from C3G-F(+) SPA-1(-/-) HPC recipients expressed high levels of Notch1 with characteristic mutations resulting in the C-terminal truncation. This proliferation was inhibited completely in the presence of a gamma-secretase inhibitor. Transplantation of Rag2(-/-) SPA-1(-/-) HPCs expressing C3G-F also resulted in a marked expansion and transformation of DP thymocytes. The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida0konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Wang
authors.forename: Misayo
authors.initials: M
authors.lastname: Aoki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Shinozuka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000172:deficiency; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency; D051881:Receptor, Notch1 / Q000737:chemistry / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D020735:Guanine Nucleotide-Releasing Factor 2; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; C091108:Sipa1 protein, mouse; D020827:rap1 GTP-Binding Proteins