BCR/ABL→STAT5 Pathway Stimulates Helix-Loop-Helix Id-1 Protein To Enhance the MMP9 - Dependent Invasiveness of Leukemia Cells.

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays as important role in leukemogenesis (Nieborowska-Skorska et al., J.Exp.Med., 189:1229,1999). We reported before that the bcl-2 family member A1 and the proto-oncogene pim-1, the two downstream effectors of STAT5, collaborate in BCR/ABL-positive cells to induce protection from apoptosis and growth factor independence (Nieborowska-Skorska et al., Blood, 99:4531,2002). We show here that expression of the helix-loop-helix protein Id1 is enhanced by BCR/ABL in the STAT5-dependent manner. This effect requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of Id1 played a key role in the BCR/ABL-mediated cell invasion in vitro, but not in protection from apoptosis in the absence of growth factors and in promotion of growth factor-independent proliferation. Leukemogenesis in mice was prolonged after injection of BCR/ABL-positive cells, in which Id-1 was downregulated by the antisence cDNA. In addition, infiltration of central nervous system (CNS) by leukemia cells was also reduced if Id-1 was inhibited. Id1 was responsible for BCR/ABL-induced production of MMP9 metalloproteinase. Abrogation of MMP9 catalytic activity by a selective inhibitor or blocking antibody decreased the invasive capability of leukemia cells. These data indicate that BCR/ABL→STAT5→Id1→MMP9 pathway may play a critical role in the BCR/ABL-dependent leukemogenesis by regulation of the invasive capability of leukemia cells. Moreover, this pathway may protect CML cells from imatinib mesylate (IM) by facilitation of their localization in CNS, a sanctuary for leukemia cells during IM therapy.