title: Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia.
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.
authors.affiliation: Laboratory of Angiogenesis & Neurovascular Link, Vesalius Research Center (VRC), VIB, K.U. Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.forename: Behzad
authors.initials: B
authors.lastname: Kharabi Masouleh
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.forename: Sandra
authors.initials: S
authors.lastname: Cauwenberghs
authors.forename: Peter
authors.initials: P
authors.lastname: Fraisl
authors.forename: Christa
authors.initials: C
authors.lastname: Maes
authors.forename: Bart
authors.initials: B
authors.lastname: Jonckx
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Thomas
authors.initials: T
authors.lastname: Schenk
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.forename: Rita
authors.initials: R
authors.lastname: Fragoso
authors.forename: Maria
authors.initials: M
authors.lastname: De Mol
authors.forename: Karolien
authors.initials: K
authors.lastname: Beel
authors.forename: Sérgio
authors.initials: S
authors.lastname: Dias
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Tessa
authors.initials: T
authors.lastname: Holyoake
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010014:Osteolysis / Q000517:prevention & control; D010879:Piperazines / Q000627:therapeutic use*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D016328:NF-kappa B; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D010879:Piperazines; D011257:Pregnancy Proteins; D011743:Pyrimidines; D000072483:Placenta Growth Factor; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl