Mus musculus
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR001712.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) is characterized by an accumulation of aberrant myeloid cells arrested at different stages of differentiation. Therapeutic approaches that prompt AML blasts to differentiate represent an attractive opportunity in the landscape of AML therapies, as they aim to induce terminal maturation and leukemia debulking without intensive cytotoxic treatments. In the present study, we investigate the involvement of HIF1 and HIF2 transcription factors in AML pathogenesis, and position HIF2 as a novel regulator of the AML differentiation block. We performed a comparative analysis of HIF1 and HIF2 function in AML cell lines via their inhibition with genetic or pharmacological strategies and found that both factors promote AML proliferation and clonogenicity. Importantly, specific inhibition of HIF2 provokes AML cell differentiation in cell lines and patient-derived xenograft (PDX) models. Mechanistically, we found that HIF2 and EZH2, the catalytic subunit of polycomb repressive complex 2, cooperate at favoring EZH2-mediated deposition of the repressive histone mark H3K27me3 on the regulatory regions of myeloid differentiation genes. Additionally, we demonstrate that HIF2 is positively regulated by the pro-differentiation agent all-trans retinoic acid (ATRA), and its inhibition cooperates with ATRA in triggering AML cell differentiation. In conclusion, we report evidence of a new role of HIF2 in the pathogenesis of AML, by promoting an undifferentiated state via EZH2-mediated epigenetic silencing of myeloid differentiation genes. We propose that HIF2 inhibition may open new therapeutic avenues for AML treatment by licensing AML differentiation and synergizing with ATRA towards leukemia exhaustion.
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Project description:Hematopoietic cell differentiation is required for initiation of acute myeloid leukemia [Microarray expression]
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Project description:The histone-3 lysine-4 methyltransferase KMT2D is frequently mutated in human cancers. However, knowledge of its role in the initiation and maintenance of acute myeloid leukemia (AML) is incomplete. Here, we show that KMT2D is generally downregulated in human AML. Using shRNA and CRISPR/Cas9 technologies, we show that Kmt2d loss, by cooperating with Trp53 and Nf1 loss, promoted mouse acute myeloid leukemogenesis through a differentiation block of hematopoietic stem and progenitor cells. Furthermore, using a doxycycline-induced shRNA system, we show that restoring Kmt2d impairs AML maintenance. Multi-omics analyses of Kmt2d-deficient and -restored AML cells showed that Kmt2d, via histone methyltransferase activity and chromatin remodeling, epigenetically regulates the expression of genes controlling hematopoietic stem cell differentiation. Lastly, we showed that 3-Deazaneplanocin A, a histone methyltransferase EZH2 inhibitor, could specifically repress Kmt2d-deficient AML cell growth and reverse pro-leukemia programs. Thus, our study indicate Kmt2d is a tumor suppressor, whose downregulation promotes AML development through differentiation blockage.
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Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
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