A polymorphism in the 3'-untranslated region of the NPM1 gene causes illegitimate regulation by microRNA-337-5p and correlates with adverse outcome in acute myeloid leukemia.
Nucleophosmin, encoded by NPM1, is a haploinsufficient suppressor in hematologic malignancies. NPM1 mutations are mostly found in acute myeloid leukemia patients with normal karyotype and associated with favorable prognosis. A polymorphic nucleotide T deletion with unknown significance is present in the NPM1 3'-untranslated region. Here, we showed that the homozygous nucleotide T deletion was associated with adverse outcomes and could independently predict shortened survival in patients with de novo acute myeloid leukemia. Mechanistically, we demonstrated that the nucleotide T deletion created an illegitimate binding NPM1 for miR-337-5p, which was widely expressed in different acute myeloid leukemia subtypes and inhibited NPM1 expression. Accordingly, NPM1 levels were found to be significantly reduced and correlated with miR-337-5p levels in patients carrying a homozygous nucleotide T-deletion genotype. Together, our findings uncover a microRNA-mediated control of NPM1 expression that contributes to disease heterogeneity and suggest additional prognostic values of NPM1 in acute myeloid leukemia.
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
Chi Keung
CK
Cheng
Tsz Ki
TK
Kwan
Chi Ying
CY
Cheung
Kitty
K
Ng
Pei
P
Liang
Suk Hang
SH
Cheng
Natalie P H
NP
Chan
Rosalina K L
RK
Ip
Raymond S M
RS
Wong
Vincent
V
Lee
Chi Kong
CK
Li
Sze Fai
SF
Yip
Margaret H L
MH
Ng
D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011110:Polymorphism, Genetic; D055815:Young Adult
D020413:3' Untranslated Regions; D035683:MicroRNAs; C544075:Mirn337 microRNA, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin