TY - JOUR
T1 - Insight into the mechanism of AML del(9q) progression
T2 - hnRNP K targets the myeloid master regulators CEBPA (C/EBPα) and SPI1 (PU.1)
AU - Rahn, Kerstin
AU - Abdallah, Ali T.
AU - Gan, Lin
AU - Herbrich, Shelley
AU - Sonntag, Roland
AU - Benitez, Oscar
AU - Malaney, Prerna
AU - Zhang, Xiaorui
AU - Rodriguez, Ashely G.
AU - Brottem, Jared
AU - Marx, Gernot
AU - Brümmendorf, Tim H.
AU - Ostareck, Dirk H.
AU - Ostareck-Lederer, Antje
AU - Crysandt, Martina
AU - Post, Sean M.
AU - Naarmann-de Vries, Isabel S.
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
KW - AML
KW - CEBPA
KW - HNRNPK
KW - SPI1
KW - del(9q)
UR - http://www.scopus.com/inward/record.url?scp=85178412260&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178412260&partnerID=8YFLogxK
U2 - 10.1016/j.bbagrm.2023.195004
DO - 10.1016/j.bbagrm.2023.195004
M3 - Article
C2 - 38008244
AN - SCOPUS:85178412260
SN - 1874-9399
VL - 1867
JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
IS - 1
M1 - 195004
ER -