Leukemia | 2021
RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner
Abstract
t(8;21) is among the most common chromosomal translocations associated with human leukemia [1–4]. The RUNX1-ETO (RUNX1-RUNX1T1, AML1-MTG8) fusion gene, generated by t(8;21), has been extensively investigated in the field; however, its mechanistic basis remains to be fully understood. Clinical features of t(8;21) leukemia include: (1) association with acute myeloid leukemia (AML) M2 subtype in the FAB classification, characterized by granulocytic maturation in morphology, (2) positivity for the following immunophenotypic markers, HLA-DR, CD117(c-KIT), CD34, CD38, CD13, CD33, CD19, and CD56+, (3) chloroma, (4) predominant onset in adolescent and young adults (AYA), but not in aged population, (5) higher prevalence in Asia, and (6) requirement of additional genetic abnormalities such as mutations in c-KIT, FLT3, RAS, ASXL1, and ZBTB7A, -9q, or –Y [2, 3]. Although a number of attempts have been made to generate its mouse model, RUNX1-ETO induction alone did not induce leukemia in most cases [5–10]. Even when leukemia developed, the penetrance was low and the latency was 1 year or longer. In addition, leukemia phenotypes did not recapitulate clinical features. As such, no tractable murine models are currently available. We reasoned that the failure in the previous efforts for the generation of RUNX1-ETO mouse model is due to insufficient expression and inappropriate cells of origin. RUNX1-ETO mRNA amount per one single leukemia cell at clinical onset time is shown to be significantly higher than that at remission state [11]. To achieve sufficient expression, Rosa26 locus which allows for abundant expression of RUNX1-ETO was employed to generate conditional knock-in (KI) mice carrying a heterozygous floxed allele of Rosa26-LSL-RUNX1-ETO-IRES-EGFP (Fig. 1A, Tables S1 and S2, Supplementary Methods). This mouse line was crossed with eR1-CreER transgenic mice