Insight into the mechanism of AML del(9q) progression: hnRNP K targets the myeloid master regulators CEBPA (C/EBPα) and SPI1 (PU.1).

AML CEBPA HNRNPK SPI1 del(9q)

Journal

Biochimica et biophysica acta. Gene regulatory mechanisms
ISSN: 1876-4320
Titre abrégé: Biochim Biophys Acta Gene Regul Mech
Pays: Netherlands
ID NLM: 101731723

Informations de publication

Date de publication:
25 Nov 2023
Historique:
received: 12 12 2022
revised: 08 11 2023
accepted: 20 11 2023
pubmed: 27 11 2023
medline: 27 11 2023
entrez: 26 11 2023
Statut: aheadofprint

Résumé

Deletions on the long arm of chromosome 9 (del(9q)) are recurrent abnormalities in about 2 % of acute myeloid leukemia cases, which usually involve HNRNPK and are frequently associated with other known aberrations. Based on an Hnrnpk haploinsufficient mouse model, a recent study demonstrated a function of hnRNP K in pathogenesis of myeloid malignancies via the regulation of cellular proliferation and myeloid differentiation programs. Here, we provide evidence that reduced hnRNP K expression results in the dysregulated expression of C/EBPα and additional transcription factors. CyTOF analysis revealed monocytic skewing with increased levels of mature myeloid cells. To explore the role of hnRNP K during normal and pathological myeloid differentiation in humans, we characterized hnRNP K-interacting RNAs in human AML cell lines. Notably, RNA-sequencing revealed several mRNAs encoding key transcription factors involved in the regulation of myeloid differentiation as targets of hnRNP K. We showed that specific sequence motifs confer the interaction of SPI1 and CEBPA 5' and 3'UTRs with hnRNP K. The siRNA mediated reduction of hnRNP K in human AML cells resulted in an increase of PU.1 and C/EBPα that is most pronounced for the p30 isoform. The combinatorial treatment with the inducer of myeloid differentiation valproic acid resulted in increased C/EBPα expression and myeloid differentiation. Together, our results indicate that hnRNP K post-transcriptionally regulates the expression of myeloid master transcription factors. These novel findings can inaugurate novel options for targeted treatment of AML del(9q) by modulation of hnRNP K function.

Identifiants

DOI: 10.1016/j.bbagrm.2023.195004 PMID: 38008244
pubmed: 38008244
pii: S1874-9399(23)00099-8
doi: 10.1016/j.bbagrm.2023.195004
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

195004

Informations de copyright

Copyright © 2023 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Kerstin Rahn (K)

Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ali T Abdallah (AT)

Interdisciplinary Center for Clinical Research (IZKF) Aachen, RWTH Aachen University, Germany; Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.

Lin Gan (L)

Interdisciplinary Center for Clinical Research (IZKF) Aachen, RWTH Aachen University, Germany.

Shelley Herbrich (S)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Roland Sonntag (R)

Department of Internal Medicine III, University Hospital RWTH Aachen University, Aachen, Germany.

Oscar Benitez (O)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Prerna Malaney (P)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Xiaorui Zhang (X)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ashely G Rodriguez (AG)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Jared Brottem (J)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Gernot Marx (G)

Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany.

Tim H Brümmendorf (TH)

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.

Dirk H Ostareck (DH)

Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany.

Antje Ostareck-Lederer (A)

Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany.

Martina Crysandt (M)

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Aachen, Germany.

Sean M Post (SM)

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: SPost@mdanderson.org.

Isabel S Naarmann-de Vries (IS)

Department of Intensive Care Medicine, University Hospital RWTH Aachen University, Aachen, Germany; Section of Bioinformatics and Systems Cardiology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: Isabel.Naarmann-deVries@uni-heidelberg.de.

Classifications MeSH