GFI1 (Growth Factor Independent 1 Transcriptional Repressor)

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. Notably, cotreatment with TQ and ruxolitinib or OTX015 induced significantly greater survival than treatment with single agents in the NSG mice engrafted with the PDX cells. These findings clearly demonstrate the preclinical efficacy of TQ in advanced MPN-BP cells and create the rationale to further interrogate the efficacy of TQ-based combinations with the current, front-line therapies or novel agents in advanced MPNs with excess blasts.

After targeting mechanosensory-restricted Foxg1, ampullary organs formed within neuromast lines, suggesting that Foxg1 normally represses their development, whether directly or indirectly. We speculate that electrosensory organs may be the 'default' developmental fate of lateral line primordia in electroreceptive vertebrates.

Exosomal miR-142-3p suppressed glioma cell migration and invasion and stimulated apoptosis by targeting GFI1.

The use of free radical scavengers such as N-acetylcysteine (NAC) and α-tocopherol (αT) reduced ROS-induced DNA damage, particularly in GFI1-36N leukemic cells. We demonstrated that the GFI1-36N variant is associated with extensive metabolic changes that contribute to the accumulation of genetic damage.

Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via Olaparib, a PARP1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1 -36N (3-fold, p<0.01), whereas the effects were insignificant in non-malignant GFI1 -36S or GFI1 -36N cells. GFI1 -36N impedes DNA repair in AML cells, opening a novel approach to treat AML on a personalized basis by targeting DNA repair. The observed findings are currently being validated in independent patient cohorts in cooperation with other groups.

Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a PARP1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in non-malignant GFI1-36S or GFI1-36N cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat AML patients carrying the GFI1-36N variant.

Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.

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.

Cell viability assay and colony-forming unit assay were used to examine the response of GFI1-36S and GFI1-36N leukemic cells to palbociclib treatment...This could promote emergence of chromosomal aberrations and hence contribute to genomic instability of leukemic cells (Figure 1). On a therapeutic level, GFI1-36N could possibly be a marker for a specific subset of AML patients that is sensitive to CDK4/6 inhibitors.