PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy

The protein tyrosine phosphatase, non-receptor type 11 (PTPN11) gene encodes SHP-2, a phosphatase involved in many signaling pathways, with a key role in development and hematopoiesis. Somatic PTPN11 mutations were found with variable prevalences in pediatric leukemia, most frequently associated with juvenile myelomonocytic leukemia (JMML).1,2 In vitro and in vivo studies, mainly in a myeloid context, demonstrated a crucial involve- ment of PTPN11 mutations in the hyperactivation of the RAS/ERK pathway.3 The oligoclonality of transgene integration sites, and the long latency before overt leukemia in mice transduced with mutant PTPN11,3 suggested that additional molecular lesions are needed to cooperate with PTPN11 mutations in leukemogenesis. This observation is in line with the ‘two hit model’ proposed by Greaves4 for B-cell precursor childhood acute lymphoblastic leukemia (ALL), in which an initiating alteration, often occurring prenatally, gives rise to a preleukemic clone, which eventually becomes fully malignant by subsequent acquisition of other molecular alterations.