Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation

Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras[superscript G12D] in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras[superscript G12D] gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras[superscript G12D over G12D] hematopoietic cells. Modulating Nras[superscript G12D] dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras[superscript G12D]. Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers.Pfizer Inc. (PD0325901)National Institutes of Health (U.S.) (Grant R37CA72614)National Institutes of Health (U.S.) (Grant P01CA40046)National Institutes of Health (U.S.) (Grant K08CA134649)Leukemia & Lymphoma Society of America (Specialized Center of Research Award LLS 7019-04))American Lebanese Syrian Associated Charitie

Genetic variation in the Solanaceae fruit bearing species lulo and tree tomato revealed by Conserved Ortholog (COSII) markers

The Lulo or naranjilla (Solanum quitoense Lam.) and the tree tomato or tamarillo (Solanum betaceum Cav. Sendt.) are both Andean tropical fruit species with high nutritional value and the potential for becoming premium products in local and export markets. Herein, we present a report on the genetic characterization of 62 accessions of lulos (n = 32) and tree tomatoes (n = 30) through the use of PCR-based markers developed from single-copy conserved orthologous genes (COSII) in other Solanaceae (Asterid) species. We successfully PCR amplified a set of these markers for lulos (34 out of 46 initially tested) and tree tomatoes (26 out of 41) for molecular studies. Six polymorphic COSII markers were found in lulo with a total of 47 alleles and five polymorphic markers in tree tomato with a total of 39 alleles in the two populations. Further genetic analyses indicated a high population structure (with FST > 0.90), which may be a result of low migration between populations, adaptation to various niches and the number of markers evaluated. We propose COSII markers as sound tools for molecular studies, conservation and the breeding of these two fruit species

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL

Identification of a resistance gene Rpi-dlc1 to Phytophthora infestans in European accessions of Solanum dulcamara

Initial screening of 14 Solanum dulcamara accessions enabled the identification of individuals resistant and susceptible to Phytophthora infestans. Crosses between contrasting genotypes resulted in three F2–BC1 populations segregating for resistance to late blight in a laboratory assay and under field conditions. Genetic profiling of one of these populations using 128 AFLP primers generated three markers linked to the resistant phenotype. Blast analysis of the sequenced markers resulted in a plausible gene position on the distal end of the long arm of chromosome 9 that could be confirmed by CAPS markers. Thus, we describe a first resistant gene, named Rpi-dlc1, from S. dulcamara, a Solanum species native to Europe. In addition, one population was tested for broadness of resistance responses using a set of seven additional P. infestans isolates, varying in virulence. This indicated the possible presence of additional Rpi genes

Induction, rapid fixation and retention of mutations in vegetatively propagated banana.

Mutation discovery technologies have enabled the development of reverse genetics for many plant species and allowed sophisticated evaluation of the consequences of mutagenesis. Such methods are relatively straightforward for seed-propagated plants. To develop a platform suitable for vegetatively propagated species, we treated isolated banana shoot apical meristems with the chemical mutagen ethyl methanesulphonate, recovered plantlets and screened for induced mutations. A high density of GC-AT transition mutations were recovered, similar to that reported in seed-propagated polyploids. Through analysis of the inheritance of mutations, we observed that genotypically heterogeneous stem cells resulting from mutagenic treatment are rapidly sorted to fix a single genotype in the meristem. Further, mutant genotypes are stably inherited in subsequent generations. Evaluation of natural nucleotide variation showed the accumulation of potentially deleterious heterozygous alleles, suggesting that mutation induction may uncover recessive traits. This work therefore provides genotypic insights into the fate of totipotent cells after mutagenesis and suggests rapid approaches for mutation-based functional genomics and improvement of vegetatively propagated crops

Resistance to late blight and yield of population B3 potato selection in Uganda

No Abstract. African Crop Science Journal Vol. 13(2) 2005: 95-10

Adaptability of sift potato genotypes in different agro-ecologies of Uganda

No Abstract. African Crop Science Journal Vol. 13(2) 2005: 107-11

Resistance to Late Blight and Yield of Population B3 Potato Selections in Uganda

Population B3 is the most advanced source of horizontal resistance available at the International Potato Centre (CIP). In this population, testing and selection for horizontal resistance to late blight, unlike those previously applied to population A clones, were simplified significantly (P<0.05) due to the absence of known R-genes. This study, conducted in southwestern and eastern Uganda, evaluated 20 selected potato genotypes in Population B3 for late blight resistance and tuber yield. Late blight severities on many of the Population B3 genotypes were lower than on most local cultivars, including the resistant cultivar, Rutuku. Population B3 genotypes performed better when sprayed with fungicide, Mancozeb, but the reduction in late blight severities due to spraying varied with genotype and location. Although spraying did not significantly (P>0.05) increase yields, almost all genotypes gave higher yields with than without spraying, with significant (P<0.05) differences among genotypes. Population B3 entries 389746.2, 383382.44, 393371.58, 392637.10, 391002.6, 393349.63, 393617.18, 391011.17, 391580.30, 393385.39, 393339.242, 393077.54, 393280.64 and 392657.8 performed well and could be considered for on-farm trials

Adaptability of Sift Potato Genotypes in Different Agro-Ecologies of Uganda

The effect of genotype by environment interaction (G x E) on fresh tuber yield of nine Standard International Field Trials (SIFT) potato (Solanum tuberosum L.) genotypes and Kisoro, a local variety, was studied in Uganda using additive main effects and multiplicative interaction (AMMI) model 3. Results indicated that the proportion of the environmental variation was much larger than the proportion due to genotypes and the proportion due to G x E interaction was also larger than the genotype main effects. Genotypes (G), environments (E) and the G x E interactions accounted for 8.43, 57.13 and 34.44% of the treatment sums of squares, respectively. AMMI and the biplot identified genotypes 384866.5, 381381.13, 389746.2, Kisoro and 386209.10 as adapted to four environments. Test genotypes 389746.2, Robijn and 381381.13 were the most stable and had higher yields (> 19 t ha-1) than all genotypes except Torridon, which was also very unstable and specifically adapted to one environment (Kalengyere 2B). Kalengyere 1B and Wanale 2A were identified as similar environments