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Acute myeloid leukaemia (AML) is the most common aggressive human leukaemia. It is frequently characterised by the stepwise acquisition of multiple somatic mutations in stem and progenitor cells. The mechanisms by which these mutations interact to perturb normal cellular processes and drive transformation remains a key question in cancer biology. This thesis explores the co-operation between two mutations which commonly co-occur in an acute megakaryoblastic leukaemia unique to children with Down Syndrome: Gata1s and haploinsufficiency of the core cohesin component Rad21. Myeloid leukaemia of Down Syndrome (ML-DS) provides an excellent model in which to study multistep leukaemogenesis. It is biologically simpler than adult AML, comprising just three genetic events occurring in temporarily separable stages: (i) constitutive trisomy 21; (ii) an acquired truncating mutation in the transcription factor GATA1 (GATA1s) in fetal life, resulting in a preleukaemic condition, Transient Abnormal Myelopoiesis (TAM); (iii) additional somatic mutation(s) in the first 4 years of post natal life, transforming preleukaemic TAM clone(s) to ML-DS. Previous studies indicate that just one additional mutation in a cohesin complex gene may be sufficient for transformation, suggesting an important co-operative role. To address this, I first confirmed the co-existence of Gata1s and cohesin gene mutations in a large cohort of patient samples and characterised the frequency and predicted functional effect of these variants. I then explored the impact of these mutations, both alone and in combination, using a transgenic mouse model system. Combined Gata1s/cohesin mutant mice displayed a novel haematopoietic phenotype, characterised by expansion of the bone marrow megakaryocyte progenitor (MkP) compartment and abnormal differentiation and proliferation of the cells within it. Integrated molecular analysis of the MkP revealed altered gene expression profiles and chromatin accessibility, with dysregulation of a number of relevant transcription factor pathways. Significantly, both phenotypic and molecular analyses revealed a much greater effect of Gata1s plus cohesin haploinsufficiency than of either mutation alone, supporting a role for mutational co-operativity. The true nature of this interaction seems likely to be complex, potentially involving dysregulation of multiple targets and regulatory mechanisms within the cell.