Journal
BLOOD CANCER DISCOVERY
Volume 3, Issue 5, Pages 444-467Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-21-0226
Keywords
-
Categories
Funding
- NIH [CA230756, DK105134]
- Cancer Center Support Grant [P30CA013330]
- Feldstein Medical Foundation
- Leukemia Research Foundation
- training grant in Stem Cell Research by the NYSTEM [C30292GG]
Ask authors/readers for more resources
This study reveals the collaborative role of Tet2 and PU.1 in suppressing leukemogenesis and the significance of a methylation-sensitive PU.1-dependent gene network in myeloid leukemia.
Cytosine hypermethylation in and around DNA-binding sites of master transcription factors, including PU.1, occurs in aging hematopoietic stem cells following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase ten-eleven translocation-2 (TET2), albeit functional relevance has been unclear. We show that Tet2-deficient mouse hematopoietic stem and progenitor cells undergo malignant transformation upon compromised gene regulation through heterozygous deletion of an upstream regulatory region (URE delta/WT) of the PU.1 gene. Although compatible with multilineage blood formation at young age, Tet2-deficient PU.1 URE delta/WT mice develop highly penetrant, transplantable acute myeloid leukemia (AML) during aging. Leukemic stem and progenitor cells show hypermethylation at putative PU.1-binding sites, fail to activate myeloid enhancers, and are hallmarked by a signature of genes with impaired expression shared with human AML. Our study dem-onstrates that Tet2 and PU.1 jointly suppress leukemogenesis and uncovers a methylation-sensitive PU.1-dependent gene network as a unifying molecular vulnerability associated with AML. SIGNIFICANCE: We identify moderately impaired PU.1 mRNA expression as a biological modality pre-disposing Tet2-deficient hematopoietic stem and progenitor cells to malignant transformation. Our study furthermore uncovers a methylation-sensitive PU.1 gene network as a common feature of myeloid leukemia potentially allowing for the identification of patients at risk for malignant transformation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available