Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition

Jan Vorwerk, Kaiyan Sun, Daria Frank, Felix Neumann, Jana Hüve, Paulina Marie Budde, Longlong Liu, Xiaoqing Xie, Pradeep Kumar Patnana, Helal Mohammed Mohammed Ahmed, Bertram Opalka, Georg Lenz, Ashok Kumar Jayavelu, Cyrus Khandanpour*

*Korrespondierende/r Autor/-in für diese Arbeit

Abstract

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.

OriginalspracheEnglisch
Aufsatznummer903691
ZeitschriftFrontiers in Oncology
Jahrgang12
ISSN2234-943X
DOIs
PublikationsstatusVeröffentlicht - 08.08.2022

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)
  • Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)

DFG-Fachsystematik

  • 205-14 Hämatologie, Onkologie

Zitieren