Figure 7.
The combination of TMZ and olaparib shows synergistic effect on GFI1-36N leukemic cells in vitro and in vivo. (A) Analysis of possible drug targets of the differently expressed DNA repair–related proteins (results from the proteomic analysis of GFI1-36S and GFI1-36N leukemic BM cells). (B) CFU assay results of murine Lin– cells after treatment with either the combination of 10 μg/mL TMZ and 0.2 μM olaparib (Olap) or DMSO as a control. n = 3, mean ± SD (C) CFU assay results from MLL-AF9 BM cells from mice that received transplantation after treatment with either 10 μg/mL TMZ (n = 2), 0.2 μM Olap (n = 2), or the combination of both (n = 3, triplicate) and as a control DMSO (n = 3). Colony number was determined, and treated samples were calculated relative to the control. mean ± SD (D) CFU assay results from K562 cells expressing GFI1-36S and GFI1-36N, treated with 10 μg/mL TMZ and 0.2 μM Olap. Relative colony numbers were calculated with respect to DMSO control (n = 3, triplicate). (E) Primary human GFI1-36S (GFI1-36S/S: 2 × BM and 2 × peripheral blood) and GFI1-36N (GFI1-36S/N: 1 × BM and 1 × SPL and GFI1-36N/N: 2 × peripheral blood) cells from patients with AML were plated 14 days in methylcellulose media and treated as described in (B). Number of live cells was determined, and treated samples were calculated relative to the control. n = 4; mean ± SD. (F) AML-free survival of mice that received transplantatiob with TMZ and Olap treatment or without. GFI1-36S or GFI1-36N MLL-AF9 BM cells were transplanted into sublethally irradiated WT mice and on day 3 after transplantation, the treatment with 100 mg/kg olaparib and 50 mg/kg TMZ was started. n = 6. (G) In an ongoing clinical trial (NCT04207190) of treating patients with AML with talazoparib along with gemtuzumab ozogamicin, 3 out of 4 GFI1-36N patients showed CRi, whereas 1 out of 12 GFI1-36S patients showed CRi. (H) Scheme elucidates GFI1-36N influence on DNA repair and genome stability in AML cells compared with GFI1-36S. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. FDA, Food and Drug Administration; SPL, spleen. Scheme created with BioRender.com.

The combination of TMZ and olaparib shows synergistic effect on GFI1-36N leukemic cells in vitro and in vivo. (A) Analysis of possible drug targets of the differently expressed DNA repair–related proteins (results from the proteomic analysis of GFI1-36S and GFI1-36N leukemic BM cells). (B) CFU assay results of murine Lin– cells after treatment with either the combination of 10 μg/mL TMZ and 0.2 μM olaparib (Olap) or DMSO as a control. n = 3, mean ± SD (C) CFU assay results from MLL-AF9 BM cells from mice that received transplantation after treatment with either 10 μg/mL TMZ (n = 2), 0.2 μM Olap (n = 2), or the combination of both (n = 3, triplicate) and as a control DMSO (n = 3). Colony number was determined, and treated samples were calculated relative to the control. mean ± SD (D) CFU assay results from K562 cells expressing GFI1-36S and GFI1-36N, treated with 10 μg/mL TMZ and 0.2 μM Olap. Relative colony numbers were calculated with respect to DMSO control (n = 3, triplicate). (E) Primary human GFI1-36S (GFI1-36S/S: 2 × BM and 2 × peripheral blood) and GFI1-36N (GFI1-36S/N: 1 × BM and 1 × SPL and GFI1-36N/N: 2 × peripheral blood) cells from patients with AML were plated 14 days in methylcellulose media and treated as described in (B). Number of live cells was determined, and treated samples were calculated relative to the control. n = 4; mean ± SD. (F) AML-free survival of mice that received transplantatiob with TMZ and Olap treatment or without. GFI1-36S or GFI1-36N MLL-AF9 BM cells were transplanted into sublethally irradiated WT mice and on day 3 after transplantation, the treatment with 100 mg/kg olaparib and 50 mg/kg TMZ was started. n = 6. (G) In an ongoing clinical trial (NCT04207190) of treating patients with AML with talazoparib along with gemtuzumab ozogamicin, 3 out of 4 GFI1-36N patients showed CRi, whereas 1 out of 12 GFI1-36S patients showed CRi. (H) Scheme elucidates GFI1-36N influence on DNA repair and genome stability in AML cells compared with GFI1-36S. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. FDA, Food and Drug Administration; SPL, spleen. Scheme created with BioRender.com.

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