PLCG1 is required for AML1-ETO leukemia stem cell self-renewal.
Tina M SchnoederAdrian SchwarzerAshok Kumar JayaveluChen-Jen HsuJoanna M KirkpatrickKonstanze DöhnerFlorian PernerTheresa EifertNicolas HuberPatricia Arreba-TutusausAnna DolnikSalam A AssiMonica NafriaLu JiangYu-Ting DaiZhu ChenSai-Juan ChenSophie G KellawayAnetta PtasinskaElizabeth S NgEdouard G StanleyAndrew G ElefantyMarcus BuschbeckHolger BierhoffSteffen BrodtGeorg MatziolisKlaus-Dieter FischerAndreas HochhausChun-Wei David ChenOlaf HeidenreichMatthias MannSteven W LaneLars BullingerAlessandro OriBjörn von EyssConstanze BoniferFlorian H HeidelPublished in: Blood (2021)
In an effort to identify novel drugs targeting fusion-oncogene induced acute myeloid leukemia (AML), we performed high-resolution proteomic analysis. In AML1-ETO (AE) driven AML we uncovered a de-regulation of phospholipase C (PLC) signaling. We identified PLCgamma 1 (PLCG1) as a specific target of the AE fusion protein which is induced after AE binding to intergenic regulatory DNA elements. Genetic inactivation of PLCG1 in murine and human AML inhibited AML1-ETO dependent self-renewal programs, leukemic proliferation, and leukemia maintenance in vivo. In contrast, PLCG1 was dispensable for normal hematopoietic stem- and progenitor cell function. These findings are extended to and confirmed by pharmacologic perturbation of Ca++-signaling in AML1-ETO AML cells, indicating that the PLCG1 pathway poses an important therapeutic target for AML1-ETO positive leukemic stem cells.
Keyphrases
- acute myeloid leukemia
- stem cells
- allogeneic hematopoietic stem cell transplantation
- high resolution
- endothelial cells
- public health
- transcription factor
- signaling pathway
- high glucose
- oxidative stress
- magnetic resonance imaging
- mass spectrometry
- computed tomography
- acute lymphoblastic leukemia
- induced apoptosis
- drug delivery
- diabetic rats
- cell proliferation
- cell free
- pi k akt
- contrast enhanced
- nucleic acid