Abstract
Background: AML with t(8;21)(q22;q22.1) defines a distinct disease entity within the WHO category ‘AML with recurrent genetic abnormalities’ and results in the formation of the AML1-ETO (AE) fusion transcript. Recent data showed that alternative splicing generates a truncated variant of AE, namely AML1-ETO9a (AE9a), containing an additional exon 9a. Co-expression of AE and AE9a was shown to induce a more aggressive leukemic phenotype with a rapid onset of AML in a retrovirally transduced mouse model (Yan et al., Nat Med 2006). However, the clinical relevance of the alternatively spliced AE9a isoform in adult patients (pts) with t(8;21) AML is not well determined yet.Aim: We sought to assess the incidence and prognostic significance of AE9a co-expression in the context of clinical and genetic factors in a large clinically well-annotated cohort of pts with t(8;21) AML.Methods: 129 pts were included based on the availability of a diagnostic bone marrow (BM) or peripheral blood (PB) sample; all pts were either enrolled on an AMLSG clinical trial protocol (n=93) or received standard intensive chemotherapy regimens. AE9a mRNA transcript levels (TL) were determined by quantitative reverse transcription PCR (qRT-PCR) using TaqMan technology. Co-expression of AE9a as a fraction of the full-length AE transcript was reported as AE9a / AE ratio (%). ABL gene expression was used as housekeeping control. Additional gene mutation data were available for KIT, FLT3 -ITD/TKD, NRA S, and ASXL2 .Results: The median age of the pts was 49 years (yrs; range, 18-75 yrs); the alternatively spliced isoform AE9a was identified in all pts; the AE9a / AE ratio (range 3%-77%, median 32%) did not significantly differ between BM (n=116, range 8%-77%, median 31%) and PB (n=13, range 3%-66%, median 52%). Median AE9a / AE ratio was not correlated with clinical features (sex, age, WBC, platelets, BM blasts) or gene mutations affecting KIT (p=0.10), FLT3 -ITD/TKD (p=0.77) or ASXL2 (p=1.00); pts with an additional NRAS mutation showed higher AE9a / AE ratios as compared to wild-type pts (median, 44% vs 31%) without reaching statistical significance (p=0.06). Using Cox regression analysis, AE9a / AE ratios were not associated with the clinical endpoints overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR). The same remained true when performing univariate analyses comparing AE9a / AE ratios dichotomized at the median (AE9a / AE>median vs AE9a / AE≤median): AE9a / AE had no impact on 4-yr OS (71% vs 79%; p=0.37), 4-yr EFS (59% vs 67%; p=0.83), and 4-yr CIR (32% vs 33%; p=0.35). Correlation of AE9a / AE ratios according to quartiles of distribution did also not affect OS (p=0.14), EFS (p=0.67), and CIR (p=0.70). Finally, we evaluated a possible correlation between AE9a / AE ratio and NRAS or KIT mutations which frequently co-occur in this AML subtype. In a subgroup analysis according to KIT or NRAS mutation status, no significant differences with regard to the clinical endpoints OS, EFS and CIR were found between AE9a / AE>median and AE9a / AE≤median.Conclusion: Alternative splicing of the AML1-ETO fusion transcript is a common feature in pts with t(8;21) AML. This finding is also supported by a recent collaborative transcriptome study where novel high-throughput sequencing (HTS) technologies were applied (Faber et al., Nat Genet 2016). Using different explorative approaches, AE9a has no impact on clinical outcome which precludes its potential as a novel independent prognostic marker in this AML subtype.MA was supported by the Else Kröner-Forschungskolleg. DisclosuresKindler:Novartis: Membership on an entity's Board of Directors or advisory committees. Lübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid. Fiedler:Amgen, Pfizer: Research Funding; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Patents & Royalties; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Griesshammer:Gilead: Consultancy, Honoraria, Speakers Bureau; Baxalta: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; AOP Orphan: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; Takeda: Honoraria, Research Funding; BMS, Amgen: Honoraria. Döhner:Amgen: Honoraria; Celator: Honoraria; Pfizer: Research Funding; Seattle Genetics: Honoraria; Bristol Myers Squibb: Research Funding; Abbvie: Honoraria; Sunesis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria; Boehringer Ingelheim: Research Funding; Astex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arog Pharmaceuticals: Honoraria, Research Funding. Döhner:Novartis: Honoraria, Research Funding.
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