Characterizing the Molecular Role of MTF2 in Refractory AML and Hematopoiesis
Creators: name: Caballero Gomez, Alejandro
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2023
Subjects: MTF2
Hematopoiesis
AML
H3K27me3
Fetal Liver
Oxidative Phosphorylation

description: Hematopoietic stem cells (HSC) are capable of self-replicating, as well as differentiating into more mature blood cells throughout the biological process known as hematopoiesis. Although the hematopoietic system has been deeply studied, there are still many knowledge gaps regarding its regulation and the behavior of hematopoietic pathologies such as leukemias. Our research group has previously shown through in vivo studies that the epigenetic regulator metal response element binding transcription factor 2 (MTF2) plays a critical role in erythropoiesis as Mtf2-null embryos die at e15.5 due to severe anemia. Here, we further studied the impact of Mtf2 in fetal hematopoietic development using our Mtf2 knock-out (KO) mouse model using cell-based assays and single-cell RNA sequencing (scRNA-seq). We demonstrated that loss of Mtf2 caused an imbalance in the HSC population, showing a decrease in long and short-term HSCs, while increasing the percentage of late multipotent progenitors, suggesting that loss of Mtf2 promotes HSC differentiation. Furthermore, gene set enrichment analysis revealed that Mtf2⁻ᐟ⁻ HSCs significantly overexpressed genes involved in oxidative phosphorylation (OxPhos), suggesting that metabolic dysregulation could be responsible for the decrease of HSCs. This was explored using flow cytometry analysis of mitochondrial membrane potential and ROS accumulation. Additionally, we showed in previous studies that decreased MTF2 expression is associated with chemoresistant acute myeloid leukemia (AML), a cancer characterized by abnormal and uncontrolled proliferation of non-functional myeloblasts. Patient sample analysis suggests that decreased expression of MTF2 impairs the deposition of Histone 3 lysine-27 trimethylation (H3K27me3), disturbing global histone methylation levels and thus gene expression profiles. We discovered that MDM2, a p53 inhibitor, is upregulated in MTF2-deficient AML. Thus, MTF2-deficient leukemia cells can avoid p53-mediated apoptosis following treatment with induction chemotherapy (IC) drugs and are refractory to treatment. Here we studied MTF2, H3K27me3 and CD92 (a downstream target of MTF2) expression as diagnostic biomarkers for refractory AML and determined their ability to predict patient response to IC and a novel combination therapy of IC and an MDM2 inhibitor. Although the biomarkers showed some accuracy at predicting patient response to IC, the size and imbalance of our sample group may be affecting the statistical significance of the results. Therefore, further analysis is encouraged to determine the statistical validity of the biomarkers as response predictors and markers of residual disease. Overall, this project explores the role of Mtf2 in hematopoiesis to better understand the function of Mtf2/PRC2-mediated epigenetic regulation underlying normal hematopoiesis and leukemogenesis and evaluates its potential as a refractory AML biomarker with the intent of improving targeted therapies and patient prognosis.