Modeling and therapeutic targeting of t(8;21) AML with/without TP53 deficiency

Int J Hematol. 2024 Aug;120(2):186-193. doi: 10.1007/s12185-024-03783-3. Epub 2024 May 3.

Abstract

Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-ETO is one of the most common subtypes of AML. Although t(8;21) AML has been classified as favorable-risk, only about half of patients are cured with current therapies. Several genetic abnormalities, including TP53 mutations and deletions, negatively impact survival in t(8;21) AML. In this study, we established Cas9+ mouse models of t(8;21) AML with intact or deficient Tpr53 (a mouse homolog of TP53) using a retrovirus-mediated gene transfer and transplantation system. Trp53 deficiency accelerates the in vivo development of AML driven by RUNX1-ETO9a, a short isoform of RUNX1-ETO with strong leukemogenic potential. Trp53 deficiency also confers resistance to genetic depletion of RUNX1 and a TP53-activating drug in t(8;21) AML. However, Trp53-deficient t(8;21) AML cells were still sensitive to several drugs such as dexamethasone. Cas9+ RUNX1-ETO9a cells with/without Trp53 deficiency can produce AML in vivo, can be cultured in vitro for several weeks, and allow efficient gene depletion using the CRISPR/Cas9 system, providing useful tools to advance our understanding of t(8;21) AML.

Keywords: AML; CRISPR/Cas9; Mouse model; RUNX1-ETO; TP53.

MeSH terms

  • Animals
  • Chromosomes, Human, Pair 21* / genetics
  • Chromosomes, Human, Pair 8* / genetics
  • Core Binding Factor Alpha 2 Subunit* / deficiency
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Disease Models, Animal*
  • Humans
  • Leukemia, Myeloid, Acute* / etiology
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / therapy
  • Mice
  • Oncogene Proteins, Fusion / genetics
  • Translocation, Genetic*
  • Tumor Suppressor Protein p53* / deficiency
  • Tumor Suppressor Protein p53* / genetics

Substances

  • Tumor Suppressor Protein p53
  • Core Binding Factor Alpha 2 Subunit
  • Trp53 protein, mouse
  • Oncogene Proteins, Fusion