Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice

Daisuke Ishida, Kohei Kometani, Hailin Yang, Kiyokazu Kakugawa, Kyoko Masuda, Kazuhiro Iwai, Misao Suzuki, Shigeyoshi Itohara, Tatsutoshi Nakahata, Hiroshi Hiai, Hiroshi Kawamoto, Masakazu Hattori, Nagahiro Minato

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

Abstract

SPA-1 (signal-induced proliferation-associated gene-1) is a principal Rap1 GTPase-activating protein in hematopoietic progenitors. SPA-1-deficient mice developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia (CML) in chronic phase, CML in blast crisis, and myelodysplastic syndrome as well as anemia. Preleukemic SPA-1-deficient mice revealed selective expansion of marrow pluripotential hematopoietic progenitors, which showed abnormal Rap1GTP accumulation. Overexpression of an active form of Rap1 promoted the proliferation of normal hematopoietic progenitors, while SPA-1 overexpression markedly suppressed it. Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo. These results unveiled a role of Rap1 in myeloproliferative stem cell disorders and a tumor suppressor function of SPA-1.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalCancer Cell
Volume4
Issue number1
DOIs
Publication statusPublished - 01-07-2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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