Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma

• Published in: Blood Vol. 105; no. 12; pp. 4836 - 4844
• Main Authors: Adamia, Sophia, Reiman, Tony, Crainie, Mary, Mant, Michael J., Belch, Andrew R., Pilarski, Linda M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-06-2005; The Americain Society of Hematology; The American Society of Hematology
• Subjects: Alternative Splicing; Biological and medical sciences; Blotting, Western; Bone Marrow - metabolism; Cell Line, Tumor; Cloning, Molecular; Codon; Codon, Terminator; DNA - metabolism; DNA Primers - chemistry; Electrophoresis, Capillary; Gene Expression Regulation, Neoplastic; Glucuronosyltransferase - biosynthesis; Glucuronosyltransferase - genetics; Hematologic and hematopoietic diseases; Humans; Hyaluronan Synthases; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Introns; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes, Mononuclear - metabolism; Medical sciences; Mitosis; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Neoplasia; Paraproteinemias - pathology; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Time Factors; Treatment Outcome; Human; Immunopathology; Alternative splicing; Immunoglobulinopathy; Pathophysiology; Lymphoproliferative syndrome; Genetics; Malignant hemopathy; Mutation; Myeloma; Monoclonal gammopathy of undetermined significance
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-10-3825

In this study, we show that the hyaluronan synthase 1 (HAS1) gene undergoes aberrant intronic splicing in multiple myeloma (MM). In addition to HAS1 full length (HAS1FL), we identify 3 novel splice variants of HAS1, HAS1Va, HAS1Vb, and HAS1Vc, detected in patients with MM or monoclonal gammopathy of undetermined significance (MGUS). HAS1Vb and HAS1Vc undergo intronic splicing with creation of a premature stop codon. MM cells expressing one or more HAS1 variants synthesize extracellular and/or intracellular hyaluronan (HA). Expression of the HAS1Vb splice variant was significantly correlated with reduced survival (P = .001). Together, alternative HAS1 gene splicing, the correlations between HAS1 splicing and HA synthesis, and the correlations between HAS1 splicing and reduced survival of MM patients support the hypothesis that the family of HAS1 protein plays a significant role in disease progression. Further, expression of HAS1Vb, in conjunction with HAS1FL and/or other HAS1 variants, may lead to accumulation of intracellular HA molecules and an impact on receptor for HA-mediated motility (RHAMM)-mediated mitotic abnormalities in MM. This study highlights the potential importance of HAS1 and its alternative splicing in pathophysiology of MGUS and MM. (Blood. 2005;105: 4836-4844)