casein-kinase-ii and Chromosome-Deletion

Topics: Abnormalities, Multiple; Casein Kinase II; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 6; Craniofacial Abnormalities; Gene Deletion; Humans; Intellectual Disability; Male; Megalencephaly; Musculoskeletal Abnormalities; Phenotype; Syndrome

A mechanism for clonal growth advantage in isolated del(5q) disease remains elusive. CSNK1A1 resides on the critically deleted region, and deletion of this gene has been shown in mouse knockout and transplantation studies to produce some characteristics of bone marrow failure, including a proliferative advantage. We aimed to establish the frequency, nature, and clinical association of CSNK1A1 mutations in patients with myelodysplastic syndrome and associated myeloid neoplasms.. Between June 1, 2004, and May 31, 2014, in King's College (London, UK), we did whole-exome sequencing of five patients with isolated del(5q) followed by targeted screening for CSNK1A1 mutations and 20 myelodysplastic syndrome-associated mutations in 245 additional patients with myeloid neoplasms. All patients met present WHO diagnostic criteria for myelodysplastic syndrome and other related myeloid neoplasms.. 39 (16%) of 250 patients with myeloid neoplasms had isolated del(5q), of whom seven (18%) had CSNK1A1 mutations. All these mutations were missense and presented in a highly conserved region that is implicated in ATP catalysis. Serial sampling and response to lenalidomide treatment showed that CSNK1A1 mutations were highly associated with the del(5q) clone. Only one patient with a CSNK1A1 mutation showed complete cytogenetic response to lenalidomide. Four (57%) of the seven patients carrying a CSNK1A1 mutation showed disease progression coupled with an increase in mutant allele burden (all four were on lenalidomide). We detected coexisting myelodysplastic syndrome-related gene mutations in patients with CSNK1A1 mutations, including TP53.. Similar to the effect of TP53 mutations on progression of del(5q) abnormality, mutant CSNK1A1 also gives rise to a poor prognosis in del(5q) abnormality, for which a coupled increase in P53 activation is suggested. CSNK1A1 mutations in del(5q) disease are important in the context of therapeutic manipulation and need incorporation into future prospective studies.. Leukaemia and Lymphoma Research.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Casein Kinase II; Chromosome Deletion; Chromosomes, Human, Pair 5; Female; Humans; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Prognosis; Prospective Studies; Retrospective Studies; Thalidomide; Tumor Suppressor Protein p53; Young Adult

UBF is a DNA binding protein which interacts with both the promoter and the enhancer of various vertebrate ribosomal RNA genes and functions as a transcription initiation factor for RNA polymerase I (pol I). We have purified murine UBF to apparent molecular homogeneity and demonstrate that its transactivating potential, but not its DNA binding activity, is modulated in response to cell growth. In vivo labelling experiments demonstrate that UBF is a phosphoprotein and that the phosphorylation state is different in growing and quiescent cells. We show that UBF is phosphorylated in vitro by a cellular protein kinase which by several criteria closely resembles casein kinase II (CKII). A major modification involves serine phosphoesterifications in the carboxy terminal hyperacidic tail of UBF. Deletions of this C-terminal domain severely decreases the UBF directed activation of transcription. The data suggest that phosphorylation of UBF by CKII may play an important role in growth dependent control of rRNA synthesis.

Topics: Amino Acid Sequence; Animals; Casein Kinase II; Cell Line; Cell Nucleolus; Chromosome Deletion; DNA; DNA-Binding Proteins; Molecular Sequence Data; Phosphorylation; Pol1 Transcription Initiation Complex Proteins; Protein Serine-Threonine Kinases; Recombinant Proteins; Restriction Mapping; RNA Polymerase I; Substrate Specificity; Transcription Factors; Transcription, Genetic; Transcriptional Activation