Recent data suggest that disruptions of the protein–protein interaction (PPI) interface of the SHP2 SH2 domain, rather than its enzymatic activity, may be a more effective approach to inhibiting SHP2 biological activity in the setting of mutations that are linked to childhood myelodysplastic syndromes and various forms of leukemias. This evidence concerns the gene PTPN11 and myelodysplastic syndrome.