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Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice
Ashley M Ramirez-Herrick1, Shannon E Mullican, Andrea M Sheehan
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
The NR4A subfamily of nuclear receptors (NR4A1, NR4A2, and NR4A3) function as transcription factors that transduce diverse extracellular signals into altered gene transcription to coordinate apoptosis, proliferation, cell cycle arrest, and DNA repair. We previously discovered that 2 of these receptors, NR4A1 and NR4A3, are potent tumor suppressors of acute myeloid leukemia (AML); they are silenced in human AML, and abrogation of both genes in mice leads to rapid postnatal development of AML. Reduced expression of NR4As is also a common feature of myelodysplastic syndromes (MDSs). Here we show that reduced gene dosage of NR4A1 and NR4A3 in hypoallelic (NR4A1(+/-)NR4A3(-/-) or NR4A1(-/-)NR4A3(+/-)) mice below a critical threshold leads to a chronic myeloid malignancy that closely recapitulates the pathologic features of mixed myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) with progression to AML in rare cases. Enhanced proliferation and excessive apoptosis of hematopoietic stem cells and myeloid progenitors, together with elevated DNA damage, contribute to MDS/MPN disease. We identify the myeloid tumor suppressor genes Egr1 and JunB and the DNA damage checkpoint kinase, polo-like kinase 2 (Plk2) as deregulated genes whose disrupted signaling probably contributes to MDS/MPN. These mice provide a novel model to elucidate the molecular pathogenesis of MDS/MPN and for therapeutic evaluation.
Insights
Reduced dosage of NR4A nuclear receptors (NR4A1, NR4A3) causes chronic myeloid malignancies, mimicking myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). This research offers a new model for studying MDS/MPN and evaluating therapies.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- The NR4A nuclear receptor subfamily (NR4A1, NR4A2, NR4A3) regulates critical cellular processes including apoptosis, proliferation, and DNA repair.
- NR4A1 and NR4A3 are established tumor suppressors in acute myeloid leukemia (AML), with their silencing observed in human AML.
- Reduced expression of NR4A nuclear receptors is also frequently seen in myelodysplastic syndromes (MDSs).
Purpose of the Study:
- To investigate the role of reduced NR4A gene dosage in myeloid malignancies.
- To establish a mouse model for mixed myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).
- To identify molecular pathways contributing to MDS/MPN pathogenesis.
Main Methods:
- Generation and analysis of hypoallelic NR4A1 and NR4A3 mice (NR4A1(+/-)NR4A3(-/-) or NR4A1(-/-)NR4A3(+/-)).
- Assessment of hematopoietic stem cell and myeloid progenitor behavior, including proliferation, apoptosis, and DNA damage.
- Gene expression analysis to identify deregulated genes in the developed myeloid malignancies.
Main Results:
- Reduced NR4A1/NR4A3 gene dosage below a critical threshold induced chronic myeloid malignancies resembling MDS/MPNs.
- These malignancies exhibited enhanced proliferation, excessive apoptosis of hematopoietic stem cells and myeloid progenitors, and elevated DNA damage.
- Deregulated expression of myeloid tumor suppressor genes Egr1 and JunB, and DNA damage checkpoint kinase Plk2, was identified.
Conclusions:
- A critical threshold of NR4A1 and NR4A3 gene dosage is essential for preventing myeloid malignancies.
- NR4A deficiency contributes to MDS/MPN pathogenesis through altered hematopoietic stem cell function and DNA damage.
- These NR4A-deficient mice provide a valuable preclinical model for MDS/MPN research and therapeutic development.
