Identification of basophils as a major source of hepatocyte growth factor in chronic myeloid leukemia: a novel mechanism of BCR-ABL1-independent disease progression.
Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
Sabine
S
Cerny-Reiterer
Viviane
V
Ghanim
Gregor
G
Hoermann
Karl J
KJ
Aichberger
Harald
H
Herrmann
Leonhard
L
Muellauer
Andreas
A
Repa
Christian
C
Sillaber
Andrew F
AF
Walls
Matthias
M
Mayerhofer
Peter
P
Valent
D001491:Basophils / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology
D007377:Interleukin-3; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D016044:Fusion Proteins, bcr-abl