VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome
- 15 August 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (4), 1238-1250
- https://doi.org/10.1182/blood-2006-02-003772
Abstract
Leukemia cell motility and transendothelial migration into extramedullary sites are regulated by angiogenic factors and are considered unfavorable prognostic factors in acute leukemias. We have studied cross talk among (1) the vascular endothelial growth factor receptor-1, FLT-1; (2) the human eag-related gene 1 (hERG1) K+ channels; and (3) integrin receptors in acute myeloid leukemia (AML) cells. FLT-1, hERG1, and the β1 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 FLT-1 signaling activation and AML cell migration. Both effects were inhibited when hERG1 channels were specifically blocked. A FLT-1/hERG1/β1 complex was also observed in primary AML blasts, obtained from a population of human patients. The co-expression of FLT-1 and hERG1 conferred a pro-migratory phenotype to AML blasts. Such a phenotype was also observed in vivo. The 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 higher probability of relapse and shorter survival periods. We conclude that in AML, hERG1 channels mediate the FLT-1–dependent cell migration and invasion, and hence confer a greater malignancy.Keywords
This publication has 46 references indexed in Scilit:
- VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary diseaseBlood, 2006
- Fetal Stromal–Dependent Paracrine and Intracrine Vascular Endothelial Growth Factor-A/Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Proliferation and Motility of Human Primary Myeloma CellsCancer Research, 2005
- The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implicationsBlood, 2005
- VEGF-induced phosphorylation of Bcl-2 influences B lineage leukemic cell response to apoptotic stimuliLeukemia, 2005
- Extramedullary Leukemia in Children With Newly Diagnosed Acute Myeloid LeukemiaJournal of Pediatric Hematology/Oncology, 2003
- The biology of VEGF and its receptorsNature Medicine, 2003
- Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromesBlood, 2001
- Angiogenesis in acute and chronic leukemias and myelodysplastic syndromesBlood, 2000
- Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migrationJCI Insight, 2000
- Early response to therapy and outcome in childhood acute lymphoblastic leukemiaCancer, 1997