Abstract
Imatinib has revolutionized the treatment of Bcr-Abl1(+) chronic myeloid leukemia (CML), but, in most patients, some leukemia cells persist despite continued therapy, while others become resistant. Here, we report that PlGF levels are elevated in CML and that PlGF produced by bone marrow stromal cells (BMSCs) aggravates disease severity. CML cells foster a soil for their own growth by inducing BMSCs to upregulate PlGF, which not only stimulates BM angiogenesis, but also promotes CML proliferation and metabolism, in part independently of Bcr-Abl1 signaling. Anti-PlGF treatment prolongs survival of imatinib-sensitive and -resistant CML mice and adds to the anti-CML activity of imatinib. These results may warrant further investigation of the therapeutic potential of PlGF inhibition for (imatinib-resistant) CML.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides
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Bone Marrow Cells / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Fusion Proteins, bcr-abl / physiology*
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Humans
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / etiology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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NF-kappa B / physiology
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Osteolysis / prevention & control
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Piperazines / therapeutic use*
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Placenta Growth Factor
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Pregnancy Proteins / antagonists & inhibitors
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Pregnancy Proteins / blood
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Pregnancy Proteins / physiology*
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Pyrimidines / therapeutic use*
Substances
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Benzamides
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NF-kappa B
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PGF protein, human
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Pgf protein, mouse
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Piperazines
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Pregnancy Proteins
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Pyrimidines
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Placenta Growth Factor
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Imatinib Mesylate
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Fusion Proteins, bcr-abl