Identification of new target molecules PTK2, TGFBR2 and CD9 overexpressed during advanced bone marrow remodelling in primary myelofibrosis.
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by remodelling of the bone marrow, including progressive myelofibrosis and exaggerated angiogenesis. Advanced PMF frequently shows a full-blown fibre meshwork, which avoids aspiration of cells, and the expression profile of genes related to stroma pathology at this stage remains largely undetermined. We investigated bone marrow core biopsies in PMF showing various degrees of myelofibrosis by custom-made low density arrays (LDA) representing target genes with designated roles in synthesis of extracellular matrix, matrix remodelling, cellular adhesion and motility. Among a set of 11 genes up-regulated in advanced stages of PMF (P < or = 0.01) three candidates, PTK2 protein tyrosine kinase 2 (PTK2), transforming growth factor beta type II receptor (TGFBR2) and motility-related protein-1 (CD9 molecule, CD9), were investigated in more detail. PTK2, TGFBR2 and CD9 were significantly overexpressed in larger series of advanced PMF stages (P < or = 0.01 respectively). Endothelial cells of the increased microvessel network in PMF could be identified as a predominant source for PTK2, TGFBR2 and CD9. CD9 also strongly identified activated fibroblasts in advanced myelofibrosis. We conclude that PTK2, TGFBR2 and CD9 represent new target molecules involved in bone marrow remodelling of PMF and warrant further investigation for potential targeted therapy.
Bock
Oliver
O
Institute of Pathology, Hannover Medical School, Hannover, Germany. Bock.Oliver@MH-Hannover.de
Muth
Michaela
M
Theophile
Katharina
K
Winter
Melissa
M
Hussein
Kais
K
Büsche
Guntram
G
Kröger
Nicolaus
N
Kreipe
Hans
H
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics*; D001856:Bone Marrow Examination; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D016022:Case-Control Studies; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000032:analysis / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011336:Probability; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000737:chemistry; D060245:Tetraspanin 29; D015854:Up-Regulation
D015703:Antigens, CD; C554869:CD9 protein, human; D008562:Membrane Glycoproteins; D018125:Receptors, Transforming Growth Factor beta; D060245:Tetraspanin 29; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II