U2af1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice.

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant-expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of WT U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1(S34F)-expressing cells were also more sensitive to reduced expression of WT U2AF1 than nonmutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the WT U2af1 allele was deleted compared with when it was not deleted. These results suggest that selectively targeting the WT U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

Low back pain after spinal fusion and Harrington instrumentation for idiopathic scoliosis.

We reviewed 41 patients with adolescent idiopathic scoliosis treated with spinal fusion and Harrington instrumentation between 1973 and 1992. The mean follow-up was 23 (11-30) years. All patients completed self-administered questionnaires, Oswestry Low Back Pain Disability Score (ODS), Roland Morris score (RLS), and Visual Analog Pain Intensity Scale (VAS). We found a high degree of satisfaction with more than three quarters of the patients in work. The outcome of ODS, RLS, and VAS showed low scores. We found a significant correlation between the scores and the Cobb angle preoperatively as well as at follow-up. The patient-oriented outcome did not correlate with the type of curve, extension of vertebral fusion, tilt angle of the lowest instrumented vertebra, postoperative Cobb angle, loss of correction, or lumbar lordosis. This long-term follow-up of Harrington rod fusion for adolescent idiopathic scoliosis showed no important impairment of health-related quality of life.