Children with the common inherited disorder neurofibromatosis, type 1 (NF1) are predisposed to myeloid leukemia, particularly juvenile chronic myelomonocytic leukemia (JMML). The NF1 gene (NF1) encodes a GTPase activating protein (GAP) called neurofibromin that stimulates GTP hydrolysis on the p21ras (Ras) family of signaling proteins. We have shown that NF1 functions as a tumor suppressor gene in myeloid cells by negatively regulating Ras. In the current period of support, we have exploited a murine model to investigate mechanistic questions related to the role of NF1 in myeloid growth control and to perform preclinical studies of rational therapeutics. These studies strongly implicate the growth factor GM-CSF as playing a central role in the aberrant growth of murine NF1 mutant cells and in human JMML. In the competing renewal of this translational research project, we will extend these studies using expertise and reagents developed during the past 4 years. This application has 4 specific aims. The experiments proposed under aim 1 involve detailed mechanistic studies of the effects of NF1 inactivation on signal transduction, apoptosis, and cell cycle control in myeloid lineage cells. We will also take a genetic approach to test the role of GM-C SF signaling in a myeloproliferative disorder (MPD) that arises in JunB mutant mice.
In aim 2, we propose studies to elucidate the role of GM-CSF in fetal liver cell engraftment that might be relevant to the pathogenesis of JMML.
Our third aim proposes a combination of in vivo and in vitro approaches to contrast the effects of expressing oncogenic Ras and inactivating NF1 in myeloid cells. These studies will exploit a novel mouse model developed by our collaborator Tyler Jacks.
In aim 4, we examine how the adapter molecule p62DOK regulates myeloid growth by interacting with the Ras GTPase activating protein p12OGAP. Together, these studies will provide new insights into how Ras signaling is normally regulated in myeloid cells, and how hyperactive Ras contributes to leukemogenesis.
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