The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements

Haematologica. 2022 Aug 1;107(8):1758-1772. doi: 10.3324/haematol.2021.276048.

Abstract

Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary samples from patients as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chromosome 3 abnormalities. Furthermore, we showed that NRIP1 knockdown negatively affects the proliferation and survival of 3qrearranged AML cells and increases their sensitivity to all-trans retinoic acid, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations
  • Chromosomes / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / pathology
  • MDS1 and EVI1 Complex Locus Protein / genetics
  • Nuclear Receptor Interacting Protein 1* / genetics
  • Nuclear Receptor Interacting Protein 1* / metabolism
  • Receptors, Retinoic Acid / genetics

Substances

  • MDS1 and EVI1 Complex Locus Protein
  • NRIP1 protein, human
  • Nuclear Receptor Interacting Protein 1
  • Receptors, Retinoic Acid

Grants and funding

Funding: SG is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation – project 446251518), the Michael Smith Foundation for Health Research (MSFHR) and the Lotte & John Hecht Memorial Foundation (project RT-2020-0578). AR was supported by the DFG (SFB 1074, project A5, and the gender equality program SFB 1074, project Z2). FK was supported by the DFG (SFB 1074, project A5), the BC Cancer Foundation and the Leukemia & Lymphoma Society of Canada.