Lessons of Nature in Trisomy-8 MDS and AML: Determinants of Clonal Drive

The clinical consequences of trisomy 8 (+8) are reflected by its categorization as an intermediate risk cytogenetic abnormality in AML while in MDS it has a more favorable impact. Gain of chromosome (chr.) 8 is a frequent event in other hematologic disorders and its prognostic role seems to be depen...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.5707-5707
Main Authors: Awada, Hussein, Kubota, Yasuo, Gurnari, Carmelo, Bravo-Perez, Carlos, Unlu, Serhan, Guarnera, Luca, Dima, Danai, Durmaz, Arda, Awada, Hassan, Maciejewski, Jaroslaw P., Visconte, Valeria
Format: Article
Language:English
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Summary:The clinical consequences of trisomy 8 (+8) are reflected by its categorization as an intermediate risk cytogenetic abnormality in AML while in MDS it has a more favorable impact. Gain of chromosome (chr.) 8 is a frequent event in other hematologic disorders and its prognostic role seems to be dependent on disease context. Some molecular lesions ( RUNX1, ASXL1) are distinctive of +8 AML and important in delineating its clinical phenotype and prognosis. However, the intrinsic molecular drivers contributing to clonal pathogenesis of myeloid neoplasia (MN) as repercussion of gain of chr.8 remain unclear. We stipulated that the study of clinical, genomic, and transcriptomic features of +8 MN will provide important clues to the pathogenesis of +8 and help refine its clinical implications in a specific clinical context. NGS and clinical data from a cohort of 3971 MDS and 3973 AML patients were reviewed, including normal karyotype MDS/AML (NK MDS or AML), isolated +8 (iso +8 MDS/AML), and non-isolated +8 (non-iso +8 MDS/AML). In addition, RNASeq data were available in a subcohort of patients (82: +8; 617 NK MDS). Expression of chr.8 genes was studied to unmask culprit genes in +8 MN. Compared to NK-AML, iso +8 AML patients were older (76% aged >60 years, P= .0005) and had more dysplastic than hyperproliferative phenotype as they presented with lower WBC (median: 9.5 vs 15.2x10 9/L, P= .008) and platelet counts (median: 49 vs 64 x10 9/L, P= .0002). Iso +8 AML had higher percentages of secondary AML (sAML, 17 vs 11%, P= .001) arising from antecedent MDS (14 vs 9%, P= .002) vs NK AML. As expected, survival analysis showed iso +8-AML to have worse median overall survival (mOS) vs NK AML (20 vs 32 months, P= .0001). Yet, when sub-classifying AML based on disease ontogeny (primary vs secondary), a significant mOS difference was only seen in primary AML (21.5 vs 34.5 months, P= .0002; in sAML, 14.7 vs 24.3 months, P= .3). As for molecular associations, a variety of mutations were more frequent in iso +8 AML vs NK AML, including: lineage transcriptional factors ( RUNX1, 33 vs 17%, P< .0001), chromatin modifiers ( ASXL1 37 vs 13%, P< .0001; EZH2 10 vs 3.4%, P< .0001), splicing factors ( SRSF2 30 vs 13%, P< .0001; U2AF1, 12 vs 3%, P< .0001) and cohesin genes ( STAG2, 13 vs 7%, P= .02). In contrast, mutations in FLT3 (33 vs 42%, = .01), DNMT3A (24 vs 35%, P=.002), NPM1 (14 vs 44%, P
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-190773