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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4836-4844.
Prepublished online as a Blood First Edition Paper on February 24, 2005; DOI 10.1182/blood-2004-10-3825.
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Submitted October 4, 2004
Accepted January 28, 2005
Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma
Sophia Adamia, Tony Reiman, Mary Crainie, Michael J Mant, Andrew R Belch, and Linda M Pilarski*
Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, AB, Canada
Department of Medicine, University of Alberta, Edmonton, AB, Canada
* Corresponding author; email: lpilarsk{at}ualberta.ca.
In this study, we show that the hyaluronan synthase1 (HAS1) gene undergoes aberrant intronic splicing in MM. In addition to HAS1 full length (HAS1FL), we identify three 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. Expression of the HAS1Vb splice variant was significantly correlated with reduced survival (p=0.001). 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 play 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 RHAMM-mediated mitotic abnormalities in MM. This study highlights the potential importance of HAS1 and its alternative splicing in pathophysiology of MGUS and MM.
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