Publications (3)20.28 Total impact
-
Article: Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling.
[show abstract] [hide abstract]
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.Blood 04/2008; 111(5):2878-86. · 9.90 Impact Factor -
Article: Generation of a conditional knockout allele for mammalian Spen protein Mint/SHARP.
[show abstract] [hide abstract]
ABSTRACT: The Spen protein family is found in worms, flies, and mammals, and is implicated in diverse biological processes from embryogenesis to aging. Spen proteins have three N-terminal RNA recognition motifs and a C-terminal SPOC domain. The mammalian Spen proteins Mint and its human ortholog SHARP interact with the Notch-signaling mediator RBP-J as well as Msx2 and several unliganded nuclear hormone receptors, and impart transcription-repressing activity to these molecules by recruiting corepressors through the SPOC domain. Despite these in vitro findings, Mint/SHARP's physiological role is largely unknown, because Mint germline knockouts are embryonic lethal. To analyze Mint/SHARP function in postnatal mice, we created Mint-floxed mice that allow the Cre/loxP-mediated conditional knockout of Mint. We analyzed Mint and RBP-J epistasis during Notch-dependent splenic B-lymphocyte development, and found that Mint suppresses Notch signaling through RBP-J. In addition, Mint deficiency caused severe hypoplasia in postnatal brain, suggesting it may regulate neuronal cell survival.genesis 06/2007; 45(5):300-6. · 2.53 Impact Factor -
Article: Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model.
[show abstract] [hide abstract]
ABSTRACT: SPA-1 is a negative regulator of Rap1 signal in hematopoietic cells, and SPA-1-deficient mice develop myeloproliferative disorders (MPD) of long latency. In the present study, we showed that the MPDs in SPA-1(-/-) mice were associated with the increased hematopoietic stem cells expressing LFA-1 in bone marrow and their premature mobilization to spleen with extensive extramedullary hematopoiesis, resembling human chronic myelogenous leukemia (CML). We further showed that human BCR-ABL oncogene caused a partial down-regulation of endogenous SPA-1 gene expression in mouse hematopoietic progenitor cells (HPC) and immature hematopoietic cell lines. Although both BCR-ABL-transduced wild-type (wt) and SPA-1(-/-) HPC rapidly developed CML-like MPD when transferred to severe combined immunodeficient mice, the latter recipients showed significantly increased proportions of BCR-ABL(+) Lin(-) c-Kit(+) cells compared with the former ones. Serial transfer experiments revealed that spleen cells of secondary recipients of BCR-ABL(+) wt HPC failed to transfer MPD to tertiary recipients due to a progressive reduction of BCR-ABL(+) Lin(-) c-Kit(+) cells. In contrast, SPA-1(-/-) BCR-ABL(+) Lin(-) c-Kit(+) cells were sustained at high level in secondary recipients, and their spleen cells could transfer MPD to tertiary recipients, a part of which rapidly developed blast crisis. Present results suggest that endogenous SPA-1 plays a significant role in regulating expansion and/or survival of BCR-ABL(+) leukemic progenitors albeit partial repression by BCR-ABL and that Rap1 signal may represent a new molecular target for controlling leukemic progenitors in CML.Cancer Research 11/2006; 66(20):9967-76. · 7.86 Impact Factor
