TY - JOUR
T1 - Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia
AU - Papaioannou, Dimitrios
AU - Ozer, Hatice G.
AU - Nicolet, Deedra
AU - Urs, Amog P.
AU - Herold, Tobias
AU - Mrózek, Krzysztof
AU - Batcha, Aarif M.N.
AU - Metzeler, Klaus H.
AU - Yilmaz, Ayse S.
AU - Volinia, Stefano
AU - Bill, Marius
AU - Kohlschmidt, Jessica
AU - Pietrzak, Maciej
AU - Walker, Christopher J.
AU - Carroll, Andrew J.
AU - Braess, Jan
AU - Powell, Bayard L.
AU - Eisfeld, Ann Kathrin
AU - Uy, Geoffrey L.
AU - Wang, Eunice S.
AU - Kolitz, Jonathan E.
AU - Stone, Richard M.
AU - Hiddemann, Wolfgang
AU - Byrd, John C.
AU - Bloomfield, Clara D.
AU - Garzon, Ramiro
N1 - Publisher Copyright:
2022 Ferrata Storti Foundation
PY - 2022/5
Y1 - 2022/5
N2 - Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clinical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymidine variant was also found to associate with better outcome in an independent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant versions of the SNHG15 lncRNA. In keeping with its negative prognostic impact, overexpression of the wild-type SNHG15 associated with higher proliferation rate of leukemic blasts when compared with the cytosine-to-thymidine variant. We conclude that recurrent genetic variants of lncRNA that are expressed in the leukemic blasts of CN-AML patients have prognostic and potential biological significance.
AB - Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clinical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymidine variant was also found to associate with better outcome in an independent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant versions of the SNHG15 lncRNA. In keeping with its negative prognostic impact, overexpression of the wild-type SNHG15 associated with higher proliferation rate of leukemic blasts when compared with the cytosine-to-thymidine variant. We conclude that recurrent genetic variants of lncRNA that are expressed in the leukemic blasts of CN-AML patients have prognostic and potential biological significance.
UR - http://www.scopus.com/inward/record.url?scp=85129715785&partnerID=8YFLogxK
U2 - 10.3324/haematol.2021.266643
DO - 10.3324/haematol.2021.266643
M3 - Article
C2 - 34261293
AN - SCOPUS:85129715785
SN - 0390-6078
VL - 107
SP - 1034
EP - 1044
JO - Haematologica
JF - Haematologica
IS - 5
ER -