Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.

Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis, type 1 (NF1). The NF1 tumor suppressor gene encodes neurofibromin, which regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on Ras proteins. The purpose of this study was to determine if the NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. Single-stranded conformational polymorphism analysis was used to detect RAS point mutations in these samples. We confirmed mutations of NF1 in three leukemias, one of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested and this suggests that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in four patients; as expected, none of these samples harbored NF1 mutations. Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are consistent with the existence of NF1 mutations in approximately 30% of JMML cases.

Functional hyperactivity of monocytes after bone marrow transplantation: possible relevance for the development of post-transplant complications or relapse.

Bone marrow transplant (BMT) complications such as graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytomegalovirus (CMV) infection are associated with high levels of circulating tumour necrosis factor-alpha (TNF), much of which may be monocyte derived. We therefore studied monocyte activation after BMT in 36 patients (18 allografts and 18 autografts); plasma neopterin and in vitro secretion of superoxide, neopterin and TNF by peripheral blood monocytes were assessed. Monocyte respiratory burst was raised at regeneration but returned to near-normal within 7 days. Plasma neopterin, and in vitro secretion of neopterin and TNF, were greater than twice normal at regeneration and remained raised for up to 6 weeks after BMT. Plasma neopterin was higher following allogeneic BMT than autologous BMT and was independent of GVHD or VOD. Low levels were seen in one patient who failed to engraft. There is evidence of increased activation of monocytes at the time of and for several weeks after engraftment post-BMT. Abnormal monocyte activation may predispose to, rather than result from, the development of complications in the early post-transplant period.