Fig. 2: Uhrf1 is required for the maintenance and progression of AML in mouse models of AE9a- or MLL-AF9-driven leukemia.
From: Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia
a The strategy of AE9a-expressing fetal liver cell transplantation (FLT) or MLL-AF9-expressing BM cell transplantation (BMT). Poly(I:C) was injected to AE9a recipients or MLL-AF9 recipients on week 4 or week 2 respectively. b Conditional deletion of Uhrf1 by poly(I:C) treatment significantly prolongs the survival time of recipient mice transplanted with AE9aUhrf1fl/fl Mx1-Cre (n = 12) or MLL-AF9Uhrf1fl/fl Mx1-Cre (n ≥ 16) cells. c The expression of Uhrf1 is minimal in the sorted GFP+ cells isolated from the spleen of the MLL-AF9Uhrf1fl/fl /MLL-AF9Uhrf1Δ/Δ mice. d The size and weight of the spleen were decreased in the AE9aUhrf1Δ/Δ and MLL-AF9Uhrf1Δ/Δ mice (n ≥ 3). e The WBC counts of AE9aUhrf1Δ/Δ or MLL-AF9Uhrf1Δ/Δ mice were significantly lower than AE9aUhrf1fl/fl or MLL-AF9Uhrf1fl/fl mice (n ≥ 6). f The PB, BM and spleen show less leukemia blast cells in the AE9a/MLL-AF9Uhrf1Δ/Δ mice group compared with the AE9a/MLL-AF9Uhrf1fl/fl group. g‒i Representative flow cytometry profiles (g) and quantification of the frequencies (h, i) of GFP+c-Kit+ leukemia blast cells and normal GFP−Mac1+ cells in the BM cells of AE9a/MLL-AF9Uhrf1Δ/Δ mice compared with AE9a/MLL-AF9Uhrf1fl/fl mice (n ≥ 3). j Loss of Uhrf1 significantly prolongs the survival time of recipient mice transplanted with MLL-AF9Uhrf1Δ/Δ cells compared with MLL-AF9Uhrf1fl/fl group (n = 15). k Knockdown of Uhrf1 significantly prolongs the survival time of recipient mice transplanted with AE9a cells, compared with the control shRNA (n ≥ 11). l, m The in vivo bioluminescence imaging (l) and quantification analysis (m) shows that knocking down Uhrf1 impairs the leukemia progression in recipient mice transplanted with AE9a or MLL-AF9 leukemia cells that are luciferase-positive (n = 5). Data are all presented as means ± SD. Statistical significance was evaluated by log-rank test for b, j and k. Statistical analyses were performed using Student’s unpaired t-test for e, h, i, m. *P < 0.05, **P < 0.01, ***P < 0.001.
