Page 140 - Haematologica May 2020

A. Sharma et al.
AF9 (Figure 6F).36 In agreement with this, Bcl2 and related genes were strongly down-regulated upon deletion of Mn1 in MLL-AF9 cells (Figure 2C), confirming the critical role of MN1 in Hoxa9/Meis1 regulated gene expression. We also identified putative Hoxa9/Hoxa10 targets differen- tially expressed and regulated in our gene expression data
and GSEA analysis in MLL-AF9 (Mn1wt vs. Mn1null) cells (Online Supplementary Table S7 and Online Supplementary Figure S15B and C). Significantly, more Hoxa9/Hoxa10 tar- get genes were down-regulated in MLL-AF9/Mn1null (P=0.027, from hypergeometric distribution). Thus, our data suggest that MN1 is required in MLL-r leukemia to
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Figure 4. MLL-AF9 and MLL-AF4 rearranged human leukemias also depend on Meningioma 1 (MN1). (A) Engraftment of THP-1/MN1wt and THP-1/MN1null cells in peripheral blood (PB) at four weeks [mean±standard error of mean (SEM), n=5 for THP-1/MN1wt, THP-1/MN1null clone2 and 9]. (B) Engraftment of MV-4- 11/MN1wt and MV-4-11/MN1null cells in peripheral blood (PB) at 4 and 8 weeks (mean±SEM; n=5 for MV-4-11/MN1wt, n=4 for MV-4-11/MN1null clone1 and 10). (C) Survival of mice receiving transplants of THP-1/MN1wt and THP-1/MN1null cells (log rank test); (n=5 for THP-1/MN1wt, THP-1/MN1null clone2 and 9). (D) Survival of mice receiving transplants of MV-4-11/MN1wt and MV-4-11/MN1null cells (log rank test); (n=5 for MV-4-11/MN1wt, n=4 for MV-4-11/MN1null clone1 and 10). (E) Percentage of THP-1 (MN1wt or MN1null clone) cells in bone marrow at death (mean±SEM; n=5 for THP-1/MN1wt and THP-1/MN1null clone9, n=4 for THP-1/MN1null clone2). (F) Percentage of MV-4-11 (MN1wt or MN1null clone) cells in bone marrow at death (mean±SEM; n=5 for MV-4-11/MN1wt, n=4 for MV-4- 11/MN1null clone1 and n=3 for MV-4-11/MN1null clone10). AML: acute myeloid leukemia; **P<0.01; ns: not significant.
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haematologica | 2020; 105(5)