Highlights
- •Loss of del(5q) gene, EGR1, imparts a clonal advantage to stem cells under stress.
- •Complete loss of EGR1 function is incompatible with malignant transformation.
- •EGR1 binds differentiation, inflammation, and DNA damage response genes.
- •Loss of EGR1 counteracts detrimental effects of inflammation on stem cells.
- •Enrichment of inflammatory genes within del(5q) region may confer fitness advantage.
Therapy-related myeloid neoplasms (t-MNs) share many clinical and molecular characteristics
with AML de novo in the elderly. One common factor is that they arise in the setting of chronic inflammation,
likely because of advanced age or chemotherapy-induced senescence. Here, we examined
the effect of haploinsufficient loss of the del(5q) tumor suppressor gene, EGR1, commonly deleted in high-risk MNs. In mice, under the exogenous stress of either
serial transplant or successive doses of the alkylating agent N-ethyl-nitrosourea (ENU), Egr1-haploinsufficient hematopoietic stem cells (HSCs) exhibit a clonal advantage. Complete
loss of EGR1 function is incompatible with transformation; mutations of EGR1 are rare and are not observed in the remaining allele in del(5q) patients, and complete
knockout of Egr1 in mice leads to HSC exhaustion. Using chromatin immunoprecipitation sequencing (ChIP-seq),
we identified EGR1 binding sites in human CD34+ cord blood-derived stem and progenitor cells (HSPCs) and found that EGR1 binds genes
critical for stem cell differentiation, inflammatory signaling, and the DNA damage
response. Notably, in the chromosome 5 sequences frequently deleted in patients, there
is a significant enrichment of innate and inflammatory genes, which may confer a fitness
advantage in an inflammatory environment. Short hairpin RNA (shRNA)-mediated silencing
of EGR1 biases HSPCs toward a self-renewal transcriptional signature. In the absence of EGR1, HSPCs are characterized by upregulated MYC-driven proliferative signals, downregulated
CDKN1A (p21), disrupted DNA damage response, and downregulated inflammation—adaptations anticipated
to confer a relative fitness advantage for stem cells especially in an environment
of chronic inflammation.
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Article info
Publication history
Published online: August 19, 2022
Accepted:
August 12,
2022
Received in revised form:
August 11,
2022
Received:
July 12,
2022
Footnotes
The study was conceptualized and supervised by AS and MML. Experiments were performed and data were collected by AS, AAF, and EMD. Bioinformatic analysis was performed by MEM and AS. Formal analysis was done by AS, MEM, and MML. The article was written by AS and MML and edited by MEM.
Identification
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© 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
