title: Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations.
abstract: Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry "hot spot" method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF > PV > ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: ρ = 0.491, p < 0.001; CD105-MVD: ρ = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs.
authors.affiliation: Clinic for Hematology, Clinical Center of Serbia, Koste Todorovica 2, Belgrade, 11000, Serbia. danijela.lekovic@yahoo.com.|Medical Faculty, University of Belgrade, Belgrade, Serbia. danijela.lekovic@yahoo.com.
authors.forename: Danijela
authors.initials: D
authors.lastname: Lekovic
authors.affiliation: Clinic for Hematology, Clinical Center of Serbia, Koste Todorovica 2, Belgrade, 11000, Serbia.|Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Gotic
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Radek
authors.initials: R
authors.lastname: Skoda
authors.affiliation: Clinic for Endocrinology, Diabetes and Metabolic Diseases, Genetic laboratory, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Bojana
authors.initials: B
authors.lastname: Beleslin-Cokic
authors.affiliation: Medical Faculty, University of Belgrade, Belgrade, Serbia.|Institute for Medical Statistics, University of Belgrade, Belgrade, Serbia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Milic
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Olivera
authors.initials: O
authors.lastname: Mitrovic-Ajtic
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Ronny
authors.initials: R
authors.lastname: Nienhold
authors.affiliation: Clinic for Hematology, Clinical Center of Serbia, Koste Todorovica 2, Belgrade, 11000, Serbia.
authors.forename: Dijana
authors.initials: D
authors.lastname: Sefer
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Suboticki
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Marijana
authors.initials: M
authors.lastname: Buac
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Markovic
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Diklic
authors.affiliation: Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Vladan P
authors.initials: VP
authors.lastname: Cokic
mesh_terms: D000328:Adult; D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D001853:Bone Marrow / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D055806:Microvessels / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000097:blood* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000097:blood / Q000473:pathology; D011446:Prospective Studies
chemical_list: D043925:Angiogenesis Inducing Agents
keywords: Angiogenesis; CALR; JAK2V617F; Microvessel density; Myeloproliferative neoplasms