PUBLICATION
Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos
- Authors
- Belt, A.J., Grant, S., Tombes, R.M., Rothschild, S.C.
- ID
- ZDB-PUB-240604-3
- Date
- 2024
- Source
- PLoS Genetics 20: e1011308e1011308 (Journal)
- Registered Authors
- Rothschild, Sarah Chase, Tombes, Robert M.
- Keywords
- none
- MeSH Terms
-
- Animals
- Bridged Bicyclo Compounds, Heterocyclic*/pharmacology
- Cyclin-Dependent Kinase 9*/antagonists & inhibitors
- Cyclin-Dependent Kinase 9*/genetics
- Cyclin-Dependent Kinase 9*/metabolism
- Embryo, Nonmammalian
- Flavonoids/pharmacology
- Histone-Lysine N-Methyltransferase/genetics
- Histone-Lysine N-Methyltransferase/metabolism
- Humans
- Leukemia, Myeloid, Acute*/drug therapy
- Leukemia, Myeloid, Acute*/genetics
- Leukemia, Myeloid, Acute*/metabolism
- Myeloid Cells/drug effects
- Myeloid Cells/metabolism
- Myeloid-Lymphoid Leukemia Protein*/genetics
- Myeloid-Lymphoid Leukemia Protein*/metabolism
- Oncogene Proteins, Fusion*/genetics
- Oncogene Proteins, Fusion*/metabolism
- Piperidines/pharmacology
- Proto-Oncogene Proteins c-bcl-2*/genetics
- Proto-Oncogene Proteins c-bcl-2*/metabolism
- Sulfonamides/pharmacology
- Zebrafish*/embryology
- Zebrafish*/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 38829886 Full text @ PLoS Genet.
Citation
Belt, A.J., Grant, S., Tombes, R.M., Rothschild, S.C. (2024) Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos. PLoS Genetics. 20:e1011308e1011308.
Abstract
Acute myeloid leukemia (AML) accounts for greater than twenty thousand new cases of leukemia annually in the United States. The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes. In this study we investigated the expression of human MLL-ENL and MLL-AF9 in the myeloid lineage of zebrafish embryos. We observed an expansion of MLL positive cells and determined these cells colocalized with the myeloid markers spi1b, mpx, and mpeg. In addition, expression of MLL-ENL and MLL-AF9 induced the expression of endogenous bcl2 and cdk9, genes that are often dysregulated in MLL-r-AML. Co-treatment of lyz: MLL-ENL or lyz:MLL-AF9 expressing embryos with the BCL2 inhibitor, Venetoclax, and the CDK9 inhibitor, Flavopiridol, significantly reduced the number of MLL positive cells compared to embryos treated with vehicle or either drug alone. In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consist with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping