Page 141 - Haematologica May 2020

MLL-rearranged AML requires MN1
maintain expression of the distal Hoxa cluster and Meis1 and as a co-factor of the Hoxa9/Meis1 transcriptional com- plex and their target genes, which also includes MLL.
Meningioma 1 as therapeutic target in MLL-AF9 acute myeloid leukemia
To evaluate MN1 as a therapeutic target in MLL positive AML, we tested the effect of MN1 siRNA in primary
human AML cells. As a proof of principle, we first tested MN1 knockdown using LNP packaged with anti-MN1 siRNA in the ME-1 cell line, which expresses MN1 at high levels. MN1 expression was reduced up to 4-fold in anti- MN1 siRNA treated cells as compared to control siRNA treated cells (Online Supplementary Figure S16A). Furthermore, we evaluated the effect of MN1 knockdown in CD34+ hematopoietic progenitor cells from four
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Figure 5. Meningioma 1 (MN1) overexpression restores leukemogenicity in MLL-AF9/Mn1null cells. (A) Cumulative cell counts of MLL-AF9/Mn1wt and MLL- AF9/Mn1null cells transduced with control or MN1MIY plasmid [mean±standard error of mean (SEM), n=3]. (B) Colony-forming cell (CFC) counts of MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells transduced with control or MN1MIY plasmid (mean±SEM, n=3). (C) Morphology of representative CFC colonies of MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells transduced with control or MN1MIY plasmid. Black scale bar represents 0.25 mm. (D) Engraftment of MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells transduced with control or MN1MIY plasmid in peripheral blood (PB) at 4 and 8 weeks after transplantation (mean±SEM of the indicated number of mice). (E) Survival of mice receiving transplants of MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells transduced with control or MN1MIY plasmid (log-rank test). **P<0.01; ns: not significant.
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