How do cohesin gene mutations contribute to myeloid leukaemogenesis? (360G-Wellcome-109187_Z_15_Z)

All germ and somatic cells require the cohesin complex for appropriate chromosomal segregation. Cohesin also plays poorly characterised roles in transcriptional regulation. Recurrect aquired mutations in cohesin complex occurs in ~10% of adult Acute Myeliod Leukemia (AML) and ~70% of children with Myeliod Leukemia of Down Syndrome (ML-DS).The mechanisms by which cohesin peturb normal haemopoiesis and contribute to leukemic transformation are poorly understood.ML-DS is an excellent model to study cohesin function. ML-DS requires just three genetic events at temporally seperable stages: (i) consistutive trisomy 21; (ii) aquired mutation in the haemopoietic transcription factor GATA1 (GATA1s) presulting in a preleukaemic condition, Transient Abnormal Myelopoesis (TAM); (iii) additional somatic mutation(s) transforming preleukaemic TAM clone(s) to ML-DS.At transformation, often only one additional mutation in genes encoding cohesin complex proteins is required; commonly loss-of-function mutations occur in the cohesin gene, RAD21.Aims:To define the:(i) Haemopoietic phenotype of loss of RAD21 function in a conditional mouse mouse model.(ii) Cooperative phenotypic effect of Gata1s and a cohesin mutation in mouse models.(iii) Molecular mechanisms of (i) and (ii). At a minimum, this will involve study of cell cycle and global gene transcription by RNA-sequencing in highly purified haemopoietic populations.