Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling

Blood
Shu-Fang WangN Minato

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...Continue Reading

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Citations

Apr 23, 2013·Experimental Cell Research·Nagahiro Minato
May 12, 2009·Cell Communication and Signaling : CCS·Raymond B BirgeShinya Tanaka
Feb 6, 2010·Expert Review of Anticancer Therapy·Kanya Honoki
Nov 29, 2008·Cancer Science·Nagahiro Minato, Masakazu Hattori
Mar 4, 2011·Bioscience Reports·Vegesna RadhaKotagiri Sasikumar
Feb 9, 2021·Molecular & Cellular Oncology·Arturo CarabiasJosé M de Pereda

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