No abstract

Oncogenic NRAS mutations are frequently identified in myeloid diseases involving monocyte lineage. However, its role in the genesis of these diseases remains elusive. We report a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the Nras locus. Approximately 95% of recipient mice develop a myeloproliferative disease resembling the myeloproliferative variant of chronic myelomonocytic leukemia (CMML), with a prolonged latency and acquisition of multiple genetic alterations, including uniparental disomy of oncogenic Nras allele. Based on singlecell profiling of phospho-proteins, a novel population of CMML cells is identified to display aberrant granulocyte-macrophage colony stimulating factor (GM-CSF) signaling in both the extracellular signalregulated kinase (ERK) 1/2 and signal transducer and activator of transcription 5 (Stat5) pathways. This abnormal signaling is acquired during CMML development. Further study suggests that aberrant Ras/ERK signaling leads to expansion of granulocytic/monocytic precursors, which are highly responsive to GM-CSF. Hyperactivation of Stat5 in CMML cells is mainly through expansion of these precursors rather than up-regulation of surface expression of GM-CSF receptors. Our results provide insights into the aberrant cytokine signaling in oncogenic NRASassociated myeloid diseases. (Blood. 2010;116(26):5991-6002) IntroductionRas proteins belong to the super family of small guanosine-5Ј-triphosphate (GTP)ases. They cycle between the active GTP-bound form and the inactive guanosine-diphosphate-bound form. Oncogenic mutations in the 3 RAS genes (H-, N-, and K-RAS) have been identified in virtually all human cancer types, with characteristic incidences and RAS gene associations. 1 In particular, mutations in the KRAS and NRAS genes but rarely in the HRAS gene are frequently identified in myeloid disorders, including acute myeloid leukemia (AML), 2,3 atypical chronic myeloid leukemia, 4 juvenile myelomonocytic leukemia (JMML), [5][6][7] and chronic myelomonocytic leukemia (CMML). [7][8][9] Both CMML and JMML belong to the group of "mixed myelodysplastic/myeloproliferative diseases" (MPDs) as classified by the World Health Organization. 7,8 CMML primarily occurs in the elderly with median ages at presentation ranging from 65-75 years, whereas JMML exclusively affects children, typically under the age of 4 years. Despite the demographic difference, CMML and JMML share similar clinical and laboratory features, including leukocytosis, monocytosis, hepatosplenomegaly, and the absence of the BCR-ABL fusion gene.Compared with JMML, in which deregulation of Ras signaling is a central theme, 5,6,7,10 the molecular pathogenesis of CMML is more diverse and less well understood. Oncogenic mutations in the NRAS gene are frequently identified in CMML patients (17%-60%), and acquired uniparental disomy (UPD) of oncogenic NRAS allele is observed in these patients. 11 In contrast, mutations in other genes regulating cell proliferation are observed with much lower frequencies. F...

Comparative RNA sequencing analyses on two soybean genotypes with contrasting seed size across seed set, growth, and early maturation stages identified key genes, modules, and regulatory networks controlling seed development.