Biology subjects

Hongo, H.

Publications and source records attributed to Hongo, H..

3 recordsLinked to original sources

bioRxiv2023

Genome analysis of the Jomon dogs reveals the oldest domestic dog lineage in Eastern Eurasia

Dog is the oldest domesticated animal that established close relationships with humans. Due to its ancient origin, when, where, and whether a single or dual domestication event occurred is still under debate. The dogs in the Jomon period (Jomon dogs) in the Japanese archipelago had little change in morphology from 10,000 to 3,000 years ago. Therefore, we expected that the ancient genome of the Jomon dogs would provide a clue to reveal the characteristics of the ancient East Asian dogs. Here, we have sequenced the genomes of three 6000-year-old Jomon dogs, one 3000-4000-year-old Jomon dog, and four late 8th century dogs excavated in Japan. Our analyses suggest that the Jomon dogs are a distinct lineage from the previously known ancient dogs and are one of the oldest among the dogs in East Eurasian lineages. In addition, the genome of the Jomon dogs contained 9.5% of the genome of Japanese wolf ancestry due to a single introgression event. We estimated the proportion of the Jomon dog lineage genome in the genomes of dogs, which indicates that the genomic composition derived from the Jomon dog lineage is one of the major sources of modern dog genomes. Furthermore, we estimated the early admixture events of dogs in East Eurasia by analyzing the ancient genomes of the Jomon dogs. Due to the admixture events, the Jomon dog-derived genome has been one of the genomic sources of a wide range of modern dogs.

evolutionary biology↗

bioRxiv2022

Allosteric SHP2 Inhibition Increases Apoptotic Dependency on BCL2 and Synergizes with Venetoclax in FLT3- and KIT- Mutant AML

Mutations in receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppressed proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that SHP2 inhibition unveils an Achilles heel of AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in FLT3- or KIT-mutant AML cell lines, and in clinically relevant xenograft models. Our results provide new mechanistic rationale and preclinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML. SignificanceThere is an unmet need for effective therapies targeting the MAPK pathway to overcome resistance in RTK-driven AML. We report that pharmacologic co-inhibition of SHP2 and BCL2 has synergistic anti-leukemia activity in preclinical models of AML with FLT3 and KIT mutations and holds potential clinical utility.

cancer biology↗

bioRxiv2021

The Japanese wolf is most closely related to modern dogs and its ancestral genome has been widely inherited by dogs throughout East Eurasia

The Japanese wolf (Canis lupus hodophilax Temminck, 1839) was a subspecies of the gray wolf that inhabited the Japanese Archipelago and became extinct 100-120 years ago. In this study, we determined the whole genomes of nine Japanese wolves from the 19th- early 20th centuries and 11 Japanese dogs and analyzed them along with both modern and ancient wolves and dogs. Genomic analyses indicate that the Japanese wolf was a unique subspecies of the gray wolf that was genetically distinct from both modern and ancient gray wolves, lacking gene flow with other gray wolves. A Phylogenetic tree that minimizes the effects of introgression shows that Japanese wolves are closest to the dog monophyletic group among the gray wolves. Moreover, Japanese wolves show significant genetic affinities with East Eurasian dogs. We estimated the level of introgression from the ancestor of the Japanese wolves to the ancestor of East Eurasian dogs that had occurred in the transitional period from the Pleistocene to the Holocene, at an early stage after divergence from West Eurasian dog lineages. Because of this introgression, Japanese wolf ancestry has been inherited by many dogs through admixture between East Eurasian dog lineages. As a result of this heredity, up to 5.5% of modern dog genomes throughout East Eurasia are derived from Japanese wolf ancestry.

evolutionary biology↗