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. 2021 Oct;35(10):2983-2988.
doi: 10.1038/s41375-021-01268-4. Epub 2021 Jun 19.

RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner

Mohamed Gaber Abdallah  1   2   3 , Akiko Niibori-Nambu  3   4 , Mariko Morii  1 , Takako Yokomizo  1 , Tomomasa Yokomizo  1 , Takako Ideue  1 , Sho Kubota  1 , Vania Swee Imm Teoh  3 , Michelle Meng Huang Mok  3 , Chelsia Qiuxia Wang  3 , Abdellah Ali Omar  2 , Kenji Tokunaga  5 , Eisaku Iwanaga  5 , Masao Matsuoka  5 , Norio Asou  6 , Naomi Nakagata  7 , Kimi Araki  7 , Mabrouk AboElenin  2 , Sayed Hamada Madboly  2 , Goro Sashida  8 , Motomi Osato  9   10   11   12
Affiliations

RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner

Mohamed Gaber Abdallah et al. Leukemia. 2021 Oct.
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. RUNX1-ETO induces abnormal myeloid progenitor (AMP) at pre-leukemic stage.
A Schematic representation for the Rosa26-LSL(LoxP-Stop-LoxP)-RUNX1-ETO-IRES-EGFP targeted and LSL excised alleles. LoxP sequences are indicated as black triangles. In the presence of Cre recombinase, the LSL cassette is excised and the inserted RUNX1-ETO and EGFP genes are induced by ubiquitously active Rosa26 promoter. GFP serves as a surrogate marker for RUNX1-ETO expression. B Experimental design for tamoxifen (TMX) injection and follow-up intervals of serial collection of peripheral blood (PB). TMX (0.05 mg/g ×1) was intraperitoneally injected at indicated ages. Collected PB is subjected to complete blood cell counts (CBC) and flow cytometry analysis for frequency check of GFP+ cells. C Representative flow cytometry profiles at asymptomatic pre-leukemia status in the RUNX1-ETO mice showing the expansion of abnormal myeloid progenitor (AMP). Bone marrow (BM) cells collected from the RUNX1-ETO and littermate wild-type control mice in 2-week cohort at 4 weeks after TMX injection were analyzed. Contour plots at left-end two columns represent frequencies of indicated compartments of hematopoietic stem progenitor cells (HSPCs). Histograms at middle two columns exhibit frequencies of GFP+ cells in the corresponding fractions gated in the contour plots. Numbers in the histograms represent GFP percentages. (D, E) An age-dependent difference in the frequencies of AMP. Representative flow profiles for AMP at three distinct age cohorts and control (D) and mean frequencies of AMP in c-Kit+Sca-1−Lin− (KL) populations (WT, P3, 2w, n = 4; 4w, n = 3) (E) are shown. Asterisk(s) represents significant differences [*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, two-way analysis of variance (ANOVA) with subsequent Bonferroni test]. Time course kinetics of white blood cell counts (WBC) (F) and percentages of GFP+ cells (G) in the PB. Individual lines represent mean values of parameters in individual cohorts, excluding diseased mice at final stages. H Kaplan–Meier survival curves of RUNX1-ETO mice in individual cohorts. 2- and 3-week cohorts show significantly shorter survival as compared to other indicated cohorts (P3, n = 6; 2w, n = 5; 3w, n = 6; 4w, n = 10; 8w, n = 8; 16w, n = 8). Asterisk(s) represents significant differences (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, Log-rank test). Abbreviations: KL, c-Kit+Sca-1-Lin-; KSL, c-Kit+Sca-1+Lin−; LT-HSC, long-term hematopoietic stem cells; ST-HSC short term HSCs, CMP common myeloid progenitors, GMP granulocyte macrophage progenitors, MEP megakaryocyte erythrocyte progenitors.
Fig. 2
Fig. 2. RUNX1-ETO induces an age-dependent myeloid spectrum disorder.
A Incidence of indicated acute myeloid leukemia (AML) and myeloproliferative disorder (MPD) subtypes in each age cohort. B Weight of spleen and liver, white blood cells (WBC), hemoglobin (Hb), and platelet (Plt) counts of mice of indicated disease subtypes and wild type (WT). Asterisk(s) represents significant differences (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, Student t-test). C Representative flow cytometry profiles of malignant cells from indicated disease subtypes. Histograms at top row show GFP% in the BM. Contour plots below exhibit positivity for indicated antigens on total bone marrow (BM) cells. D Frequency of GFP+ cells in the BM, Spleen and peripheral blood (PB) in indicated disease subtypes. E Heatmap for the percentages of individual antigen+ cells in total BM cells (M1, n = 7; M2a, n = 9; M2b, n = 7; MPD a, n = 5; MPD b, n = 3). Asterisk(s) in white and black represents a significant increase or decrease, respectively, against the corresponding WT population [*P ≤ 0.05, two-way ANOVA with subsequent Bonferroni test]. F, G Expression levels of RUNX1-ETO in the present mouse model, human clinical cases, and commonly used experimental materials such as human leukemia cell lines (Kasumi-1 and SKNO-1) and a mouse leukemia cell line EML retrovirally traduced with RUNX1-ETO9a, in quantitative reverse transcription-polymerase chain reaction (F) and western blot analysis (G). F mRNA expression level of RUNX1-ETO is shown as % against that in Kasumi-1. BM patients, blast, or BM from mouse represent non-sorted mononuclear cells from t(8;21) leukemia patients (n = 8), sorted GFP+c-Kit+Gr1−B220− blast cells (n = 7), or non-sorted whole bone marrow cells (n = 7) from this mouse model, respectively. G Protein expression levels of RUNX1-ETO, GFP, and β-actin (an internal control) in the indicated materials are shown. %GFP in individual samples are given at the bottom of panels.
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References

    1. Metzeler KH, Bloomfield CD. Clinical relevance of RUNX1 and CBFB alterations in acute myeloid leukemia and other hematological disorders. Adv Exp Med Biol. 2017;962:175–99. doi: 10.1007/978-981-10-3233-2_12. - DOI - PubMed
    1. Bolouri H, Farrar JE, Triche T, Jr, Ries RE, Lim EL, Alonzo TA, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24:103–12. doi: 10.1038/nm.4439. - DOI - PMC - PubMed
    1. Jiang L, Li XP, Dai YT, Chen B, Weng XQ, Xiong SM, et al. Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome. Proc Natl Acad Sci USA. 2020;117:20117–26. doi: 10.1073/pnas.2003900117. - DOI - PMC - PubMed
    1. Reikvam H, Hatfield KJ, Kittang AO, Hovland R, Bruserud Ø. Acute myeloid leukemia with the t (8; 21) translocation: clinical consequences and biological implications. J Biomed Biotechnol. 2011;2011:1–23. doi: 10.1155/2011/104631. - DOI - PMC - PubMed
    1. Chin D, Watanabe-Okochi N, Wang C, Tergaonkar V, Osato M. Mouse models for core binding factor leukemia. Leukemia. 2015;29:1970. doi: 10.1038/leu.2015.181. - DOI - PubMed

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