Analysis and therapeutic targeting of the IL-1R pathway in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), a subgroup of mature T-cell neoplasms with an aggressive clinical course, is characterized by elevated expression of CD30 and anaplastic cytology. To achieve a comprehensive understanding of the molecular characteristics of ALCL pathology and to identify therapeutic vulnerabilities, we applied genome-wide CRISPR library screenings to both anaplastic lymphoma kinase positive (ALK+) and primary cutaneous (pC) ALK- ALCLs and identified an unexpected role of the interleukin-1R (IL-1R) inflammatory pathway in supporting the viability of pC ALK- ALCL. Importantly, this pathway is activated by IL-1α in an autocrine manner, which is essential for the induction and maintenance of protumorigenic inflammatory responses in pC-ALCL cell lines and primary cases. Hyperactivation of the IL-1R pathway is promoted by the A20 loss-of-function mutation in the pC-ALCL lines we analyze and is regulated by the nonproteolytic protein ubiquitination network. Furthermore, the IL-1R pathway promotes JAK-STAT3 signaling activation in ALCLs lacking STAT3 gain-of-function mutation or ALK translocation and enhances the sensitivity of JAK inhibitors in these tumors in vitro and in vivo. Finally, the JAK2/IRAK1 dual inhibitor, pacritinib, exhibited strong activities against pC ALK- ALCL, where the IL-1R pathway is hyperactivated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC-ALCL and provided opportunities for developing novel therapeutic strategies.

Author Correction: The first amber caridean shrimp from Mexico reveals the ancient adaptation of the Palaemon to the mangrove estuary environment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The first amber caridean shrimp from Mexico reveals the ancient adaptation of the Palaemon to the mangrove estuary environment.

The aquatic and semiaquatic invertebrates in fossiliferous amber have been reported, including taxa in a wide range of the subphylum Crustacea of Arthropoda. However, no caridean shrimp has been discovered so far in the world. The shrimp Palaemon aestuarius sp. nov. (Palaemonidae) preserved in amber from Chiapas, Mexico during Early Miocene (ca. 22.8 Ma) represents the first and the oldest amber caridean species. This finding suggests that the genus Palaemon has occupied Mexico at least since Early Miocene. In addition, the coexistence of the shrimp, a beetle larva, and a piece of residual leaf in the same amber supports the previous explanations for the Mexican amber depositional environment, in the tide-influenced mangrove estuary region.