Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status.
Bone marrow fibrosis in chronic idiopathic myelofibrosis (cIMF) most likely represents an imbalance between synthesis and turnover of collagen fibers. Because the JAK-STAT signaling pathway is involved in the regulation of genes encoding matrix metalloproteinases (MMPs), we examined the expression of MMPs, their tissue inhibitors (TIMPs), and collagen types in relation to the JAK2 status (V617F mutation versus wild-type) in cIMF (n = 64). Whereas no correlation was found between the JAK2 status and MMP gene products, there was an evident association with the stage of disease. Membrane type 1-MMP (MMP-14) was overexpressed by up to 80-fold in advanced stages that progressed to fibrosis (P < 0.001), and megakaryocytes and endothelial cells were unmasked as the major cellular source. By contrast, a significantly higher expression of neutrophil collagenase (MMP-8) was encountered in the prefibrotic stages of cIMF (P < 0.001). Altogether, the stepwise progress of myelofibrosis in cIMF was associated with expression of a defined subset of target genes as shown in sequential trephine biopsies of cIMF patients. We conclude that the expression of matrix-modeling genes in cIMF is not influenced by the JAK2 mutation status but is predominantly related to the stage of disease.
Bock
Oliver
O
Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. bock.oliver@mh-hannover.de
Neuse
Johanne
J
Hussein
Kais
K
Brakensiek
Kai
K
Buesche
Guntram
G
Buhr
Thomas
T
Wiese
Birgitt
B
Kreipe
Hans
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000201:enzymology; D017364:Collagenases / Q000235:genetics*; D018450:Disease Progression; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D008533:Megakaryocytes / Q000201:enzymology / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000201:enzymology* / Q000235:genetics*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017364:Collagenases; D020782:Matrix Metalloproteinases