Fig. 1 | Leukemia

Fig. 1

From: GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations

Fig. 1

Lethal acute myeloid leukemia (AML) in Npm1/Flt3-ITD mice is preceded by changes in myeloid and erythroid cells associated with GATA1 deregulation. a (i) Kaplan−Meier plot of mouse survival according to the indicated genotypes (n = 8 to 24 per genotype); Npm1+/TCTG;Flt3+/ITD mice display a median survival of 18.5 months versus 21 months of Npm1+/TCTG or Flt3+/ITD mice or 22.5 months of wild-type controls (p < 0.0001, logrank test). (ii) Changes in white blood cell (WBC) counts of Npm1+/TCTG;Flt3ITD/ITD (n = 3), Npm1TCTG/TCTG;Flt3ITD/ITD (n = 3), Npm1+/TCTG;Flt3+/ITD (n = 6) and Npm1TCTG/TCTG;Flt3+/ITD (n = 9) mice. (iii) Spleen weight to total body weight ratio in the indicated genotypes. Spleen ratio in Npm1+/TCTG;Flt3ITD/ITD (n = 3) and Npm1TCTG/TCTG;Flt3ITD/ITD (n = 4) mice was two fold greater than in Npm1+/TCTG;Flt3+/ITD (n = 5) and Npm1TCTG/TCTG;Flt3+/ITD (n = 18) leukemic mice (0.041 ± 0.014 and 0.046 ± 0.023 vs 0.017 ± 0.012 and 0.025 ± 0.016 p < 0.001 by one-way analysis of variance (ANOVA) analysis). b (i) Significant differences in WBC count in Npm1+/TCTG;Flt3+/ITD compared to Npm1+/TCTG;Flt3+/+, Npm1+/+;Flt3+/ITD and Npm1+/+;Flt3+/+ littermate groups (n = 12 to 20 per genotype); pie charts show neutrophils (N) and lymphocytes (L) percentages. (ii) Mean corpuscolar volume (MCV) values in preleukemic mice (n = 12 to 20 per genotype). (iii–v) Flow-cytometric analysis of bone marrow stem and progenitor cell compartment sizes, including long-term hematopoietic stem cells (LT-HSCs; linSca-1+c-kit+ CD34Flt3), short-term HSCs (ST-HSCs; lin-Sca-1+c-kit+CD34+Flt3), multipotent progenitors (MPPs; linSca-1+c-kit+CD34+Flt3+), granulocyte/monocyte progenitors (GMPs LinSca-1cKit+CD34+FcγRII/IIIhi) and common megakaryocyte-erythroid progenitor (MEP; LinSca-1cKit+CD34FcγRII/IIIlo) populations (n = 4 to 10 per genotype). (vi) Summary of hemopoietic changes in Npm1+/TCTG;Flt3+/ITD mice. c (i) Overlap of differently gene expression profiling (GEP) of Npm1TCTG/TCTG;Flt3+/+, Npm1+/+;Flt3+/ITD and Npm1TCTG/TCTG;Flt3+/ITD compared to Npm1+/+;Flt3+/+ (n = 3 mice for each genotype). (ii) GATA1 messenger RNA (mRNA) and protein expression in the bone marrow (BM) of the indicated genotypes. (iii) GATA1 protein expression in lineage-depleted BM cells from the indicated genotypes. d (i) Enforced expression of GATA1 protein in the BM of mice transplanted with Npm1+/TCTG;Flt3+/ITD LSK (n = 4 to 12) infected with an inducible GATA1 lentiviral system and killed 2 months after transplantation. (ii, iii) Significant differences in WBC counts, neutrophils and MCV values in the peripheral blood (PB) of GATA1-rescued mice. (iv) Frequency of MPP and GMP populations in MOCK (n = 10) and GATA1 (n = 16) infected mice. Data represent the mean ± SD. N.S. not significant; *p < 0.05, **p < 0.01, ***p < 0.001; unpaired t-test with Welch’s correction

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