BIRC5 (survivin) splice variant expression correlates with refractory disease and poor outcome in pediatric acute myeloid leukemia: A report from the Children's Oncology Group. Issue 4 (11th October 2013)

• Record Type: Journal Article
• Authors: Moore, Andrew S.; Alonzo, Todd A.; Gerbing, Robert B.; Lange, Beverly J.; Heerema, Nyla A.; Franklin, Janet; Raimondi, Susana C.; Hirsch, Betsy A.; Gamis, Alan S.; Meshinchi, Soheil
• Is Part Of: Pediatric blood & cancer. Volume 61:Issue 4(2014:Apr.)
• Page Start: 647
• Page End: 652
• Publication Date: 2013-10-11
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.24822
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="pbc24822-sec-0001" sec-type="section"> <title>Background</title> <p>The inhibitor‐of‐apoptosis protein survivin, encoded by <italic>BIRC5</italic>, regulates apoptosis, cell division and proliferation. Several survivin splice variants have been described however, the prognostic significance of their expression has not been well defined in pediatric acute myeloid leukemia (AML).</p> </sec> <sec id="pbc24822-sec-0002" sec-type="section"> <title>Procedure</title> <p>Quantitative expression analyses of <italic>BIRC5</italic> mRNA (n = 306) and survivin transcript splice variants (n = 90) were performed on diagnostic bone marrow samples from children with <italic>de novo</italic> AML treated on the clinical trials CCG‐2961 and AAML03P1, then correlated with disease characteristics and clinical outcome.</p> </sec> <sec id="pbc24822-sec-0003" sec-type="section"> <title>Results</title> <p>Total <italic>BIRC5</italic> expression did not correlate with clinical outcome. Fragment length analysis and sequencing of the entire <italic>BIRC5</italic> transcript demonstrated three splice variants. The most prominent product, wild‐type survivin, was expressed in all samples tested. Two minor transcripts were present in 90 patients treated on CCG‐2961; survivin‐2B and a novel variant, survivin‐ΔEx2, characterized by deletion of <italic>BIRC5</italic> exon II. A high 2B/ΔEx2 expression ratio (≥1) correlated with increased diagnostic WBC count, monocytic phenotype, +8 cytogenetics, lower complete remission (45% [n = 10] vs. 88% [n = 59], <italic>P</italic> < 0.001) and higher induction failure rates (23% [n = 5] vs. 3% [n = 2], <italic>P</italic> = 0.009). Consistent with this poor induction response, patients with a 2B/ΔEx2 ratio ≥1 had inferior 5‐year survival rates (OS 36% vs. 60%, <italic>P</italic> = 0.011; EFS 23% vs. 53% at 5 years, <italic>P</italic> = 0.001) and appear to have increased relapse risk (<italic>P</italic> = 0.056). Subset analyses suggest that relative over‐expression of 2B, rather than under‐expression of ΔEx2 determines clinical response.</p> </sec> <sec id="pbc24822-sec-0004" sec-type="section"> <title>Conclusions</title> <p>High survivin‐2B/ΔEx2 ratios are associated with refractory disease and inferior survival in childhood AML. Survivin splice variant expression warrants prospective evaluation in clinical trials. Pediatr Blood Cancer 2014;61:647–652. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>