Role of STAG2 in myeloid malignancies

• Main Author: Matto, Nazia
• Other Authors: Mufti, Ghulam Jeelani ; Gaymes, Terry
• Published: King's College London (University of London) 2017
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733321

Myelodysplastic syndrome (MDS), a clonal disease arising from the mutation of the haematopoietic stem cells, is characterized by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and transformation to acute myeloid leukaemia (AML). Defects in the DNA damage repair pathway in MDS and AML give rise to chromosomal instability (CI) such as aneuploidy, chromosomal translocation and loss of heterozygosity (LOH) a hallmark of human neoplasm. Cohesin a multiprotein complex responsible for tethering the sister chromatids together until their timely separation in mitosis has been linked with the phenomena of chromosomal instability. In this study, second generation sequencing (SGS) was performed in a panel of 154 MDS patients to characterize the incidence and functional consequences of cohesin mutations in myeloid malignancies. This led to the identification of mutations in three components of cohesin ring in 6% (9/154) of the patients with maximum number of mutations identified in STAG2. None of the patients with cohesin aberrations had a TP53 mutation and all the patients with cohesin mutations showed a significant progression free survival. Four of the patients showed co-existing mutations in ASXL1 (an epigenetic regulator) and SRSF2 (pre-mRNA splicing factor). To elucidate the functional consequences of STAG2 mutations and the possibility for it to be exploited synthetically as a target for therapeutic intervention two cell lines; a myeloid cell line, U937 with a stable knockdown of STAG2 and a urinary bladder cell line, UMUC3 with mutated STAG2 were used to study the effect of loss of STAG2 on homologous recombination (HR) repair of DNA, cell cycle kinetics and viability in response to DNA repair pathway inhibitors such as inhibitors of poly- ADP-ribose (PARP) and effect on the expression of other members of the cohesin complex. Knockdown of STAG2 had no effect on the recruitment of RAD51 a marker for HR, cell cycle kinetics and viability in response to treatment with PARP inhibitors. Further no effect on the expression of other members of the cohesin complex was observed upon knockdown of STAG2. The results from this study speculate STAG2 as a candidate which has a role to play in the pathogenesis of MDS not through its involvement in HR pathway but through a mechanism that needs further investigation.