BCR/ABL directly inhibits expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved in the regulation of hematopoiesis

The BCR/ABL oncogene causes chronic myelogenous leukemia (CML), a myeloprol iferative disorder characterized by clonal expansion of hematopoietic proge nitor cells and granulocyte lineage cells. The SH2-containing inositol-5-ph osphatase SHIP is a 145-kDa protein which has been shown to regulate hemato poiesis in mice. Targeted disruption of the murine SHIP gene results in a m yeloproliferative syndrome characterized by a dramatic increase in numbers of granulocyte-macrophage progenitor cells in the marrow and spleen. Also, hematopoietic progenitor cells from SHIP-/- mice are hyperresponsive to cer tain hematopoietic growth factors, a phenotype very similar to the effects of BCR/ABL in murine cells. In a series of ECR/ABL-transformed hematopoieti c cell lines, Philadelphia chromosome (Ph)-positive cell lines, and primary cells from patients with CML, the expression of SHIP was found to be absen t or substantially reduced compared to untransformed cell lines or leukemia cells lacking BCR/ABL. Ba/F3 cells in which expression of BCR/ABL was unde r the control of a tetracycline-inducible promoter showed rapid loss of p14 5 SHIP, coincident with induction of BCR/ABL expression. Also, an ABL-speci fic tyrosine kinase inhibitor, CGP57148B (STI571), rapidly caused reexpress ion of SHIP, indicating that BCR/ABL directly, but reversibly, regulates th e expression of SHIP protein. The estimated half-life of SHIP protein was r educed from 18 h to less than 3 h. However, SHIP mRNA also decreased in res ponse to BCR/ABL, suggesting that SHIP protein levels could be affected by more than one mechanism. Reexpression of SHIP in BCR/ABL-transformed Ba/F3 cells altered the biological behavior of cells in culture. The reduction of SHIP due to BCR/ABL is likely to directly contribute to the pathogenesis o f CML.