Daniel, A. R. | Search bioRxiv

bioRxiv2020

Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-lymphoblastic leukemia/lymphoma. Here, we aimed to determine key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/- and KrasLA1 mice were not observed to harbor significantly higher numbers of non-synonymous somatic mutations compared to thymic lymphomas from unirradiated p53-/- mice. However, we observed distinct patterns of recurrent mutations in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Using reporter mice for activation of the Notch1 signaling we observed that TBI enriched Notch1hi CD44+ thymocytes, which are capable of self-renewal in vivo. Mechanistically, genetic inhibition of Notch1 signaling in thymocytes prevented the formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, our results demonstrate a critical role of activated Notch1 signaling in driving multi-step carcinogenesis of thymic lymphoma following total-body irradiation in p53 WT mice.

cancer biology↗

bioRxiv2020

Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis and the effect of cancer therapies on their function are not well understood. Here, we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable radiation sensitivity of myxoid liposarcomas. We identified novel interactions between FUS-CHOP and chromatin remodeling complexes that regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, co-localizes with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylate the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupts oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. SignificancePrion-like domains translocated in cancer have been shown to drive global epigenetic changes that are oncogenic. However, some translocation-driven cancers exhibit dramatic clinical responses to therapy, though the mechanism for these responses are not well-understood. Here we show that ionizing radiation can disrupt oncogenic interactions between a fusion oncoprotein and a chromatin remodeling complex, ISWI. This mechanism of disruption links phosphorylation of the prion-like domain in an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.

cancer biology↗