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The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify  ROBO1  and  ROBO2  as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with  ROBO  mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of  ROBO1  and  ROBO2  are frequently observed in patients with progression or carrying  ROBO  mutations. In  in vitro  experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that  ROBO  mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of  ROBO  mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.

Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes