ABSTRACT
Clinical treatment of acute myeloid leukemia (AML) largely relies on intensive chemotherapy. However, the application of chemotherapy is often hindered by cardiotoxicity. Patient sequence data revealed that angiotensin II receptor type 1 (AGTR1) is a shared target between AML and cardiovascular disease (CVD). We found that inhibiting AGTR1 sensitized AML to chemotherapy and protected the heart against chemotherapy-induced cardiotoxicity in a human AML cell-transplanted mouse model. These effects were regulated by the AGTR1-Notch1 axis in AML cells and cardiomyocytes from mice. In mouse cardiomyocytes, AGTR1 was hyperactivated by AML and chemotherapy. AML leukemogenesis increased the expression of the angiotensin-converting enzyme and led to increased production of angiotensin II, the ligand of AGTR1, in an MLL-AF9-driven AML mouse model. In this model, the AGTR1-Notch1 axis regulated a variety of genes involved with cell stemness and chemotherapy resistance. AML cell stemness was reduced after Agtr1a deletion in the mouse AML cell transplant model. Mechanistically, Agtr1a deletion decreased γ-secretase formation, which is required for transmembrane Notch1 cleavage and release of the Notch1 intracellular domain into the nucleus. Using multiomics, we identified AGTR1-Notch1 signaling downstream genes and found decreased binding between these gene sequences with Notch1 and chromatin enhancers, as well as increased binding with silencers. These findings describe an AML/CVD association that may be used to improve AML treatment.
Subject(s)
Cardiotoxicity , Disease Models, Animal , Leukemia, Myeloid, Acute , Receptor, Angiotensin, Type 1 , Receptor, Notch1 , Animals , Humans , Mice , Amyloid Precursor Protein Secretases/metabolism , Cardiotoxicity/metabolism , Cardiotoxicity/pathology , Cell Line, Tumor , Heart/drug effects , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Notch1/metabolism , Signal Transduction/drug effectsABSTRACT
The cucumber tapeworm Dipylidium caninum (Cestoda, Dilepididae) is a common intestinal parasite of dogs and cats and can cause dipylidiasis in humans, especially in infants and children. In this study, the complete mitogenome of this tapeworm was sequenced using next-generation sequencing technology. The entire genome was 14,226 bp in size and encoded 36 genes, including 12 protein-coding genes, 22 transfer RNA genes, and 2 ribosomal RNA genes. The phylogeny revealed that D. caninum grouped with other species from the order Cyclophyllidea and separated from species of Pseudophyllidea. Within the Dipylidiidae, both dog-originated D. caninum were phylogenetic distinctiveness from cat-originated D. caninum, suggesting that D. caninum may represent a species complex. Altogether, the complete mitogenome of D. caninum sequenced here should contribute to a better understanding of the phylogenetic and taxonomic placement of this species.
ABSTRACT
The dog roundworm Toxocara canis (Nematoda: Toxocaridae) is an important zoonotic parasitic nematode and cause toxocariasis in human with a worldwide distribution. Herein, the complete mitochondrial genome of a representative of this nematode from USA was determined through next generation sequencing platform. The whole genome was 14,309 bp in size and encoded 12 protein-coding genes, 22 transfer RNAs, and 2 ribosomal RNAs. Phylogeny showed that although T. canis from USA and Australia were more closely related to each other than to that from Chinese, three T. canis isolates clustered together and formed paraphyletic relationships with T. cati and T. malayensis, supporting them as sister species among the family Toxocaridae. These cumulative mitochondrial DNA data should contribute to a better understanding of the phylogenetic relationship of this species.
ABSTRACT
Toxascaris leonina (Nematoda, Ascarididae) is a cosmopolitan nematode of canids and felids and poses potential threats to public health due to aberrant larva migrans. Herein, the complete mitochondrial genome sequence of a representative of this nematode from the dog in China was determined using next-generation sequencing technology. The assembled genome was 14,357 bp in length and encoded 36 genes, including 12 protein-coding genes, 22 transfer RNAs and 2 ribosomal RNAs. The phylogeny revealed that the canid-originated T. leonina were phylogenetic distinctiveness from the felid-originated T. leonina within the genus Toxascaris of Ascarididae, supporting that T. leonina may represent a species complex.