GFI1 36N

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.

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.

On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

MM patients carrying gain of 1q21 (≥3 copies) demonstrated poor progression free survival. Furthermore, gene expression analysis implicated a role for GFI1-36N in epigenetic regulation and metabolism, potentially promoting the initiation and progression of MM.