Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model

Cancer Res. 2006 Oct 15;66(20):9967-76. doi: 10.1158/0008-5472.CAN-06-1346.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blast Crisis / genetics
  • Blast Crisis / metabolism
  • Blast Crisis / pathology*
  • Down-Regulation
  • Female
  • Fusion Proteins, bcr-abl / biosynthesis*
  • Fusion Proteins, bcr-abl / genetics
  • GTPase-Activating Proteins / biosynthesis
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / physiology*
  • Gene Expression Regulation, Leukemic
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Hematopoietic Stem Cells / physiology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Lymphocyte Function-Associated Antigen-1 / biosynthesis
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • GTPase-Activating Proteins
  • Lymphocyte Function-Associated Antigen-1
  • Nuclear Proteins
  • Sipa1 protein, mouse
  • Fusion Proteins, bcr-abl
  • rap1 GTP-Binding Proteins