Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells

G Bollag, DW Clapp, S Shih, F Adler, YY Zhang… - Nature …, 1996 - nature.com
G Bollag, DW Clapp, S Shih, F Adler, YY Zhang, P Thompson, BJ Lange, MH Freedman…
Nature genetics, 1996nature.com
Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including
juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene
encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we
show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-
like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity.
Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation …
Abstract
Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1−/− mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.
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