Mutatons in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1). NF1 encodes a GTPase activating protein (GAP) for p21 ras (Ras) called neurofibromin. Neurofibromin converts p21 ras from its active GTP to its inactive GDP bound conformation. Individuals with NFl have a propensity to acquire benign and malignant tumors. Additionally, children with NFl are predisposed to juvenile myelomonocytic leukemia (JMML). A hallmark of myeloid progenitors (CFU-GM) from JMML bone marrow cells is their propensity to hyperproliferate in response to low doses of the growth factor granulocyte macrophage colony stimulating factor (GM-CSF). Homozygous disruption of Nfl is lethal in utero; however we found that murine Nf1 -deficient fetal hematopoletic cells show an abnormal pattern of CFU-GM growth and hyperactivation of Ras effectors in response to multiple growth factors, including GM-CSF and stem cell factor (SCF), the ligand for the c-kit receptor tyrosine kinase. C-kit is encoded by the murine dominant white spotting locus, W). Since the W and Nfl loci appeared to function along a common developmental pathway, mice with mutations at both loci were generated. We found that haploinsufficiency of Nfl partially rescued the mast cell and coat color defects in W41 mice. These data offered genetic evidence that haploinsufficiency at Nfl modulates cell fates in vitro and in vivo in two lineages that are affected in individuals with NFl. The results support the emerging concept that heterozygous inactivation of tumor suppressor genes may have important biological effects.While loss of neurofibromin increases p21 ras activity in specific cell lineages, identification of alterations in distinct p21 ras effector pathways that control proliferation and survival in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Most previous studies argue that loss of neurofibromin results in increased activation of the classical p21 ras-Raf-Mek-ERK pathway. However, we have preliminary data to support an alternative biochemical model where the growth advantage of Nfl1-deficient cells is mediated through increased signals from p21 ras to the small Rho GTPase, Rac2, a Rac isoform expressed only in hematopoietic cells. We propose studies to examine how activation of p21 ras and Rac isoforms cooperate to alter the biology of Nfl +/- mast cells and Nf 1 -/- stem and myeloid progenitor cells utilizing mice with genetic mutations in these loci.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074177-10
Application #
7089981
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
1997-04-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
10
Fiscal Year
2006
Total Cost
$310,959
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ferguson, Michael J; Rhodes, Steven D; Jiang, Li et al. (2016) Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatr Blood Cancer 63:206-13
Zeng, Yi; Broxmeyer, Hal E; Staser, Karl et al. (2015) Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation. Stem Cells 33:1630-41
Rhodes, Steven D; Zhang, Wei; Yang, Dalong et al. (2015) Dystrophic spinal deformities in a neurofibromatosis type 1 murine model. PLoS One 10:e0119093
Molosh, Andrei I; Johnson, Philip L; Spence, John P et al. (2014) Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 17:1583-90
Staser, Karl; Park, Su-Jung; Rhodes, Steven D et al. (2013) Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest 123:329-34
Staser, Karl; Shew, Matthew A; Michels, Elizabeth G et al. (2013) A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol 41:56-66.e2
Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki et al. (2013) The tumor suppressor CDKN3 controls mitosis. J Cell Biol 201:997-1012
Yang, Feng-Chun; Staser, Karl; Clapp, D Wade (2012) The plexiform neurofibroma microenvironment. Cancer Microenviron 5:307-10
Staser, Karl; Yang, Feng-Chun; Clapp, D Wade (2012) Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression. Annu Rev Pathol 7:469-95
Robertson, Kent A; Nalepa, Grzegorz; Yang, Feng-Chun et al. (2012) Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol 13:1218-24

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