Ectopic Expression of Snail and Twist in Ph+ Leukemia Cells Upregulates CD44 Expression and Alters Their Differentiation Potential

摘要

Philadelphia chromosome-positive (Ph+) leukemia is characterized by reciprocal translocation between chromosomes 9 and 22. The resultant BCR/ABL fusion protein displays constitutive tyrosine kinase activity, leading to the induction of aberrant proliferation and neoplastic transformation. The bone marrow (BM) microenvironment is tumor-promoting, and contributes to disease recurrence in Ph+ leukemia. Activity in the BM microenvironment is mediated by several cellular compartments, extracellular matrix, various soluble factors including transforming growth factor beta 1 (TGF-β1), and the hypoxic conditions in the BM niche. TGF-β1 is released during bone remodeling and plays a role in maintaining leukemic stem cells, as well as being implicated in the epithelial-mesenchymal transition (EMT) process in most solid tumors. Although EMT is largely implicated in epithelial tumors, recent findings argue for an EMT-like process in leukemia as well. The surface receptor CD44 is involved in cell adhesion, cell migration, and homing of normal and malignant hematopoietic stem cells. Elevation of CD44 expression is considered a marker for a worse prognosis in most hematological malignancies. We explored the functions of Snail and Twist1 in Ph+ leukemia. We showed that ectopic expression of Snail and, to a lesser extent, Twist1, upregulates CD44 expression that is β-catenin-dependent. Moreover, the presence of Snail or Twist1 partially blocked phorbol 12-myristate 13-acetate-induced megakaryocyte differentiation, while that of Twist significantly altered imatinib-induced erythroid differentiation. Thus EMT modulators affected proliferation, CD44 gene expression and differentiation ability of Ph+ leukemia cells.