Association of heparanase gene (HPSE) single nucleotide polymorphisms with hematological malignancies.
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.
Ostrovsky
O
O
Laboratory of Molecular Immunobiology, Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Korostishevsky
M
M
Levite
I
I
Leiba
M
M
Galski
H
H
Vlodavsky
I
I
Nagler
A
A
D000483:Alleles; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005966:Glucuronidase / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics*; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D000099175:Heparanase
D005966:Glucuronidase; D000099175:Heparanase