Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor

MITOCHONDRIAL FRAGMENTATION IS A NEW THERAPEUTIC TARGET AND DIAGNOSTIC CRITERIA FOR MYELODYSPLASTIC SYNDROMES.

Introduction: Myelodysplastic syndromes (MDS) are characterized by persistent of cytopenia, gene abnormalities, and dysplasia. Although the correlation between chronic inflammation and ineffective hematopoiesis is demonstrated in forming MDS pathogenesis, the detailed mechanisms remain unclear. Methods: Recently, we established a new MDS with low blasts (MDS-LB) model (CBLΔE8/9-RUNX1S291fs mice) , which recapitulates MDS-LB pathogenesis such as pancytopenia and chronic inflammation, by introducing these two mutations into murine hematopoietic stem and progenitor cells (HSC/Ps) . Results: MDS model mice exhibited excessive mitochondrial fragmentation due to Drp1 activation in HSC/Ps. Importantly, pharmacological inhibition of mitochondrial fragmentation rescued leukocytopenia and dysplasia formation in MDS mice by suppressing inflammatory signaling activation, suggesting that mitochondrial fragmentation could be a new therapeutic target of MDS. Given that mitochondrial fragmentation is related to MDS pathogenesis, we hypothesized that mitochondrial fragmentation can be used for morphological diagnosis of MDS. Differential diagnosis of patients with non-MDS cytopenia and MDS-LB has been challenging. We assessed mitochondrial morphology in bone marrow samples from 10 healthy individuals and 141 patients before disease-modifying therapy. The percentage of cells with mitochondrial fragmentation was significantly increased in patients with MDS-LB, compared with that in patients with cytopenia without dysplasia and gene abnormality (mean 50.7% vs 22.4%, P<0.001, cutoff value 30.8%). The calculated cutoff value clearly distinguishes patients with MDS-LB and non-MDS cytopenia. Conclusions: These data suggest that mitochondrial fragmentation can be not only a new therapeutic target of MDS-LB but also one category of dysplasia that can diagnose MDS-LB