Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

BACKGROUND. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia. METHODS. We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced. Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF. RESULTS. Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731(Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients. In one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wild-type and mutant receptors. CONCLUSIONS. Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia

Design, specifications, and first beam measurements of the compact linear accelerator for research and applications front end

The compact linear accelerator for research and applications (CLARA) is an ultrabright electron beam test facility being developed at STFC Daresbury Laboratory. The ultimate aim of CLARA is to test advanced free electron laser (FEL) schemes that can later be implemented on existing and future short-wavelength FELs. In addition, CLARA is a unique facility to provide a high-quality electron beam to test novel concepts and ideas in a wide range of disciplines and to function as a technology demonstrator for a future United Kingdom x-ray FEL facility. CLARA is being built in three phases; the first phase, or front end (FE), comprises an S-band rf photoinjector, a linac, and an S-bend merging with the existing versatile electron linear accelerator beam line; the second phase will complete the acceleration to full beam energy of 250 MeV and also incorporate a separate beam line for use of electrons at 250 MeV; and the third phase will include the FEL section. The CLARA FE was commissioned during 2018, and the facility was later made available for user experiments. Significant advancements have been made in developing high-level software and a simulation framework for start-to-end simulations. The high-level software has been successfully used for unmanned rf conditioning and for characterization of the electron beam. This paper describes the design of the CLARA FE, performance of technical systems, high-level software developments, preliminary results of measured beam parameters, and plans for improvements and upgrades. © 2020 authors. Published by the American Physical Society