Large-Scale In Vitro and In Vivo CRISPR-Cas9 Knockout Screens Identify a 16-Gene Fitness Score for Improved Risk Assessment in Acute Myeloid Leukemia.

PURPOSE: The molecular complexity of acute myeloid leukemia (AML) presents a considerable challenge to implementation of clinical genetic testing for accurate risk stratification. Identification of better biomarkers therefore remains a high priority to enable improving established stratification and guiding risk-adapted therapy decisions. EXPERIMENTAL DESIGN: We systematically integrated and analyzed the genome-wide CRISPR-Cas9 data from more than 1,000 in vitro and in vivo knockout screens to identify the AML-specific fitness genes. A prognostic fitness score was developed using the sparse regression analysis in a training cohort of 618 cases and validated in five publicly available independent cohorts (n = 1,570) and our RJAML cohort (n = 157) with matched RNA sequencing and targeted gene sequencing performed. RESULTS: A total of 280 genes were identified as AML fitness genes and a 16-gene AML fitness (AFG16) score was further generated and displayed highly prognostic power in more than 2,300 patients with AML. The AFG16 score was able to distill downstream consequences of several genetic abnormalities and can substantially improve the European LeukemiaNet classification. The multi-omics data from the RJAML cohort further demonstrated its clinical applicability. Patients with high AFG16 scores had significantly poor response to induction chemotherapy. Ex vivo drug screening indicated that patients with high AFG16 scores were more sensitive to the cell-cycle inhibitors flavopiridol and SNS-032, and exhibited strongly activated cell-cycle signaling. CONCLUSIONS: Our findings demonstrated the utility of the AFG16 score as a powerful tool for better risk stratification and selecting patients most likely to benefit from chemotherapy and alternative experimental therapies.

Assessment of dental ontogeny in late Miocene hipparionines from the Lamagou fauna of Fugu, Shaanxi Province, China.

A collection of 28 hipparionine skull and mandible fossils with a dated age of approximately 7.4 Ma from Fugu, Shaanxi, northwestern China (belonging to Hipparion chiai and Hipparion cf. coelophyes) shows an age distribution in a successive development sequence. By observing the dentitions in these fossil materials, knowledge of dental ontogeny has been gained, such as the opening time of the posterior wall of post-fossettes, the displacement of the plis hypostyle, the morphologic changes of the protocone and hypocone, etc. Additionally, 4 isolated maxillary cheek teeth and 2 mandibular cheek teeth were cut into slices in the traditional manner for authentication. These discoveries indicate that both of the hipparionine species in the Lamagou fauna are Hipparion cf. chiai exactly and offer further insight into the morphologic changes that occur during dental wear in hipparionines, which may greatly promote the morphological and taxonomic study of hipparionine species.