Mutations of the PTPN11 Gene in Childhood Hematological Malignancies.

The PTPN11 gene encodes SHP2, which is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factors and cytokine receptors and its function is mediated, at least in part, through the Ras/Raf/ERK cascade in hematopoietic and non-hematopoietic cells. Recently, it has been reported that germline mutations in PTPN11 cause Noonan syndrome and a gain-of-function somatic mutations in PTPN11 has also been reported in juvenile myelomonocytic leukemia (JMML). To investigate the prevalence of mutations in PTPN11 in childhood acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), we screened the hot spot of PTPN11, exon 3, in 80 cell lines, including 14 AML, 5 chronic myeloid leukemia, 14 T-cell ALL and 47 B-precursor ALL cell lines, and 207 fresh samples, including 20 myelodysplastic syndrome (MDS), 3 JMML, 85 AML, 57 B-precursor ALL patients as well as 42 infant leukemia patients (6 AMLs, 35 ALLs, 1 mixed lineage leukemia), using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. In exon 3, mutations were observed in 2 of 14 (14.3%) AML cell lines (Asp61Val and Glu76Gly). A missense mutation (Ala72Val) was detected in 1 of 85 (1.2%) AML patients (a 9-year-old girl with FAB-M0). In 20 MDSs, a missense mutation (Asp61Val) (5%) was identified in a RAEB-T patient. In 3 JMMLs, 2 missense mutations (66.7%) were detected; one was Gly60Ala, and the other was Glu76Val. In 42 infant leukemia patients, we detected only one missense mutation (Ala72Asp) (2.4%) in an AML-M5b patient. However, we did not detect any mutations of exon 3 in 61 ALL cell lines and 92 ALL patients including 35 infant ALL patients. The screening for other coding regions is still undergoing although more than 90% of the reported mutations were clustered in exon 3. In conclusion, our data suggest that the PTPN11 mutations are involved in myeloid hematological malignancies rather than ALL.