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Open Access 03-05-2024 | Acute Myeloid Leukemia | Original Article

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

Authors: Wenyu Zhang, Jingmei Li, Keita Yamamoto, Susumu Goyama

Published in: International Journal of Hematology

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.

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Title: Modeling and therapeutic targeting of t(8;21) AML with/without TP53 deficiency
Authors: Wenyu Zhang
Jingmei Li
Keita Yamamoto
Susumu Goyama
Publication date: 03-05-2024
Publisher: Springer Nature Singapore
Keywords: Acute Myeloid Leukemia
Dexamethasone
Leukemia
Published in: International Journal of Hematology
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-024-03783-3

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