A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high cyclin D1 mRNA levels and preferentially express short cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are cyclin D1a isoforms with truncated 3UTRs, not alternatively spliced cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated cyclin D1 mRNAs, 7 had genomic deletions in the CCND1 3UTR region. In 3 others, CCND1 contained point mutations that created premature polyadenylation signals, giving rise to 1.5-kb mRNAs lacking most of the 3UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type cyclin D1a mRNA. Premature polyadenylation due to a 3UTR mutation also was present in the Z-138 MCL cell line, which expressed both truncated and full-length cyclin D1a mRNAs. In these cells, the half-life of the short cyclin D1a mRNA was much longer than that of the full-length mRNA. We conclude that alterations of CCND1 3UTR IntroductionMantle cell lymphoma (MCL) comprises about 6% of all nonHodgkin lymphoma and is considered incurable with standard chemotherapy. 1,2 Median survival is approximately 3 years, but survival ranges from less than one year to Ͼ 6 years. The hallmark genetic feature of MCL is the t(11;14) translocation that leads to misexpression of cyclin D1 in the malignant cells. [3][4][5] The t(11;14) is not unique to MCL and occurs also in multiple myeloma. 6 Cyclin D1 is a member of the D-type cyclins that regulate the transition from G 0 /G 1 phase to S phase of the cell cycle. 7 Cyclin D1 is not normally expressed at high levels in lymphoid cells, and its expression from the t(11;14) translocated allele is driven by enhancer elements in the immunoglobulin heavy chain locus. Most t(11;14) translocations take place at the 5Ј end of the cyclin D1 locus, but translocations at the 3Јend of the gene also have been described in some cases. 8 CCND1 has 5 exons, which can be alternatively spliced to create 2 major isoforms, cyclin D1a and D1b. The cyclin D1a isoform is 4.5 kb in length, with a coding region of only 882 bp. The majority of this mRNA consists of 3ЈUTR sequences containing mRNA destabilizing elements. The cyclin D1b isoform lacks exon 5 but retains intron 4, which contains a translation stop codon after 99 bp and a polyadenylation signal less then 300 bp 3Ј from this stop codon. The 1.7-kb cyclin D1b mRNA is found in most tumors and cell lines that express cyclin D1 and encodes a 274 amino acid protein that differs at the C terminus from the 294 amino acid protein encoded by the cyclin D1a mRNA. [9][10][11][12][13] In contrast to cyclin D1a, cyclin D1b is potently transforming in experimental models. 13,14 The relative abundance of the cyclin D1b isoform is reportedly affected by a G/A single nucleotide polymorphism at the last base of exon 4 (position 870, codon 241), which is the...
Hematopoietic stem-cell transplantation (HSCT) is associated with high rates of gonadal failure, which is distressing for younger patients desiring to start a family. The perceived importance and optimal timing of discussing fertility- and menopause-related information with women undergoing aggressive treatment such as HSCT is not well defined. Questionnaires were sent to 532 patients who underwent HSCT between January 1987 and September 2004 at the ages of 16 to 50 years. The questionnaire assessed demographic data, the need for fertility- and menopause-related information at various times during treatment, and standardized measures of anxiety, quality of life, and menopausal symptoms. The return rate was 40.2%, with 196 patients participating. Of these, 38% reported that they had discussed fertility-related issues with health-care providers since their diagnosis; 54% had discussed menopause-related issues. At the time of diagnosis, participants considered receiving information on fertility and menopause as being of equal importance. However, after HSCT, information about menopause was considered more important than information on fertility (P < or = .0001). Being <40 years, being childless, desiring to bear children in the future, and having a high score on the State-Trait Anxiety Inventory (STAI) correlated with higher ratings of importance for both fertility- and menopause-related information. Our results suggested that healthcare providers should provide information on fertility and menopause repeatedly throughout the treatment period, and that menopause-related information should be reemphasized after HSCT. Such counseling is crucial for patients who are young and childless.
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