Dose-Dependent Effects of Dnmt3a in an Inducible Murine Model of KrasG12D-Driven Leukemia

Authors

Jason H Rogers
Allison Rosen
Jaime M Reyes
Shamika Ketkar
Shannon E Conneely
Rohit Gupta
Luibin Yang
Matthew B Miller
Geraldo Medrano
Rogelio Aguilar
Nneka Uchenda
Margaret A Goodell
Rachel E Rau

Language

English

Publication Date

7-1-2024

Journal

Experimental Hematology

DOI

10.1016/j.exphem.2024.104248

PMID

38834136

PMCID

PMC11288274

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ER^T2 murine model systems to study the effects of constitutively active Kras^G12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of diverse nonhematologic tumors appearing after tamoxifen induction, we employed a transplantation model. With pretransplant tamoxifen induction, most Kras mice died quickly of T-cell malignancies regardless of Dnmt3a status. Using post-transplant induction, we observed a dose-dependent effect of DNMT3A depletion that skewed the leukemic phenotype toward a myeloid lineage— 64% of 3aKO/Kras mice had exclusively myeloid disease compared with 36% of 3aHet/Kras, and only 13% of Kras mice. 3aKO combined with Kras led to increased disease burden, multi-organ infiltration, and faster disease progression. DOT1L inhibition exerted profound anti-leukemic effects in malignant 3aKO/Kras cells, but not malignant cells with Kras mutation alone, consistent with the known sensitivity of DNMT3A-mutant leukemia to DOT1L inhibition. RNAseq from malignant myeloid cells revealed that biallelic Dnmt3a deletion was associated with loss of cell cycle regulation, MYC activation, and TNF�� signaling. Overall, we have developed a robust model system for mechanistic and preclinical investigations of AML with DNMT3A and Ras pathway lesions.

Keywords

Animals, DNA Methyltransferase 3A, Mice, Proto-Oncogene Proteins p21(ras), DNA (Cytosine-5-)-Methyltransferases, Disease Models, Animal, Mice, Transgenic, Mice, Knockout, Leukemia, Myeloid, Acute, hematologic malignancies, murine transplant models, leukemia, Kras, Dnmt3a

Published Open-Access

yes

Recommended Citation

Rogers, Jason H; Rosen, Allison; Reyes, Jaime M; et al., "Dose-Dependent Effects of Dnmt3a in an Inducible Murine Model of KrasG12D-Driven Leukemia" (2024). Children’s Nutrition Research Center Staff Publications. 289.
https://digitalcommons.library.tmc.edu/staff_pub/289