Ostrovsky O, Korostishevsky M, Levite I, Leiba M, Galski H, Vlodavsky I, Nagler A
Laboratory of Molecular Immunobiology, Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Leukemia. 2007 Nov;21(11):2296-303. doi: 10.1038/sj.leu.2404821. Epub 2007 Jul 5.
Heparanase, endo-beta-D-glucuronidase, degrades heparan sulfate glycosaminoglycans - the principal polysaccharide of the basement membrane and extracellular matrix. Heparanase activity plays a decisive role in biological processes associated with remodeling of the extracellular matrix, such as cancer metastasis, angiogenesis and inflammation. In the hematopoietic system, heparanase is thought to be associated with normal differentiation and function of myeloid cells and platelets. We investigated heparanase polymorphisms in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), Hodgkin's disease (HD) and multiple myeloma (MM). Significant correlation was found between rs11099592 and rs6535455 heparanase gene (HPSE) single nucleotide polymorphisms (SNPs) and ALL (chi2(1d.f.)=4.96, P=0.026). Genotype frequency comparisons revealed a significant association with rs4693602 (chi2(2d.f.)=7.276, P=0.026) in MM patients and rs4364254 (chi2(2d.f.)=6.226, P=0.044) in AML patients. Examination of HPSE gene mRNA expression by real-time RT-PCR indicated a significant low HPSE gene expression level in ALL patients and a high expression level in MM and AML patients, compared to healthy controls. Moreover, statistically significant correlation was found between heparanase mRNA expression level and three HPSE gene SNPs (rs4693608, rs11099592 and rs4364254) among healthy individuals. These data suggest that certain HPSE gene SNPs may contribute to basal heparanase gene expression and that alterations in this gene are an important determinant in the pathogenesis of ALL, AML and MM.
乙酰肝素酶，即内切-β-D-葡糖醛酸酶，可降解硫酸乙酰肝素糖胺聚糖，后者是基底膜和细胞外基质的主要多糖。乙酰肝素酶活性在与细胞外基质重塑相关的生物学过程中起决定性作用，如癌症转移、血管生成和炎症。在造血系统中，乙酰肝素酶被认为与髓系细胞和血小板的正常分化及功能有关。我们研究了急性髓系白血病（AML）、骨髓增生异常综合征（MDS）、急性淋巴细胞白血病（ALL）、慢性髓系白血病（CML）、霍奇金病（HD）和多发性骨髓瘤（MM）患者的乙酰肝素酶基因多态性。发现乙酰肝素酶基因（HPSE）单核苷酸多态性（SNP）rs11099592和rs6535455与ALL显著相关（卡方检验(1自由度)=4.96，P=0.026）。基因型频率比较显示，MM患者中rs4693602（卡方检验(2自由度)=7.276，P=0.026）以及AML患者中rs4364254（卡方检验(2自由度)=6.226，P=0.044）存在显著关联。通过实时逆转录聚合酶链反应（RT-PCR）检测HPSE基因mRNA表达，结果表明，与健康对照相比，ALL患者中HPSE基因表达水平显著降低，而MM和AML患者中表达水平升高。此外，在健康个体中，乙酰肝素酶mRNA表达水平与三个HPSE基因SNP（rs4693608、rs11099592和rs4364254）之间存在统计学显著相关性。这些数据表明，某些HPSE基因SNP可能影响乙酰肝素酶基因的基础表达，且该基因的改变是ALL、AML和MM发病机制中的重要决定因素。
