VEGFR-1 (FLT-1), b₁ Integrin and hERG K⁺ Channel Form a Macromolecular Signaling Complex in Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a heterogeneous group of clonal bone marrow (BM) malignancies, presenting a wide spectrum of morphologic, immunophenotypic, cytogenetic, and molecular features. There is general agreement that persistent detection of leukemia cells outside the BM microenvironment, especially when accompanied by infiltration into extramedullary sites, is a clear negative prognostic factor. Infiltration may also reduce leukemia responsiveness to induction chemotherapy. Great attention is thus being played to the molecular mechanisms that regulate acute leukemia cells exit from the BM. A crucial role is thought to be played by the angiogenic factors and angiogenesis-related signals, that operate inside the BM microenvironment.The persistence of circulating leukemia blasts and their engraftment into extramedullary sites are negative prognostic factors, in patients with acute leukemia. Leukemia cell exit from the bone marrow is regulated by angiogenic factors and in particular by the Vascular Endothelial Growth Factor and its receptor 1, FLT-1. We have studied the cross talk between

1. FLT-1,

2. the human eag-related gene 1 (hERG1) K⁺ channels,

3. integrin receptors, in acute myeloid leukemia (AML) cells.

FLT-1, hERG1 and the b₁ integrin were found to form a macromolecular signaling complex. The latter mostly recruited the hERG1B isoform of hERG1 channels, and its assembly was necessary for subsequent FLT-1 tyrosine phosphorylation and sustained AML cell migration. What is more, both effects were inhibited when hERG1 channel were specifically blocked. The formation of an FLT-1/hERG1/b₁ complex was also observed in primary AML blasts, obtained from a population of human patients. The coexpression of FLT-1 and hERG1 conferred a pro-migratory phenotype to these AML blasts. Such a phenotype was also observed in vivo. Herg1 positive blasts were more efficient in invading the peripheral circulation and the extramedullary sites after engraftment into immunodeficient mice. Moreover, herg1 expression in leukemia patients correlated with a shorter overall survival. Overall, we conclude that hERG1 channels mediate the FLT-1 dependent AML cell migration and that their expression is a negative prognostic factor, in AML.