Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.

Idiopathic eruptive macular pigmentation in a child with citrin deficiency.

Idiopathic eruptive macular pigmentation (IEMP) is a rare dermatological disorder with generally unclear etiology and pathogenesis. A 5½-year-old girl was referred to hospital with a 10 month history of brown skin rashes. In early infancy, citrin deficiency had been diagnosed with the SLC25A13 genotype c.851_854del4/c.998G > A, but all clinical and laboratory abnormalities recovered following the introduction of a lactose-free and medium-chain triglyceride-enriched formula. Physical examination at referral indicated symmetric, multiple and non-scaly brown macules on the neck, trunk, buttocks and proximal parts of the extremities. Histopathology indicated epidermal basal layer hyperpigmentation with an irregular distribution, along with a large number of melanophages in the upper dermis. The diagnosis of IEMP was thus made. Within 2 years of follow up, the rashes disappeared spontaneously and gradually. To our knowledge, this is the first description of IEMP in a patient with silent citrin deficiency.