Additional Chromosome Research Articles

Resistance of Nicotiana tabacum to Phytophthora parasitica var. nicotianae Race 0 Is Enhanced by the Addition of N. plumbaginifolia Chromosome 9 with a Slight Effect on Host Genomic Expression

ABSTRACTBlack shank is a devastating disease in tobacco production worldwide, and resistance to this disease in Nicotiana plumbaginifolia Viv. tobacco is controlled by the Php gene. The position of the Php gene on chromosomes of N. plumbaginifolia remains unclear. The tobacco line TP‐1, which was derived from N. tabacum L. cv. Yunyan87 and N. plumbaginifolia, was used in the present study to help locate the Php gene on the N. plumbaginifolia chromosomes and understand the effects of the N. plumbaginifolia chromosome addition on the genomic expression of N. tabacum. An in vitro infection test verified that TP‐1 was as resistant to Phytophthora parasitica var. nicotianae race 0 as N. plumbaginifolia and more resistant than Yunyan87. According to cytogenetic analysis, TP‐1 was identified as a monosomic alien addition line and the alien chromosome was recognized as the ninth chromosome of N. plumbaginifolia through. Thus, the P. parasitica var. nicotianae race 0 resistance gene might be Php on chromosome 9 of N. plumbaginifolia. A superficial transcriptomic analysis showed that addition of the alien chromosome slightly affected the genomic expression of the host, with only 3.32% of differentially expressed genes (DEGs) identified between TP‐1 and Yunyan87. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, most (9/13) genes classified as involved in plant–pathogen reactions, particularly five serine/threonine‐protein kinase genes, were upregulated in TP‐1. It is worth noting that flavonoid biosynthesis may be greatly downregulated in TP‐1: two genes were both downregulated in TP‐1 according to gene ontology analysis, and all 20 DEGs in the flavonoid biosynthesis pathway were downregulated in TP‐1 according to KEGG analysis.

The influence of additive clonal chromosome abnormalities in Ph negative cells on the efficacy of chronic myeloid leukemia

Objective: To investigate the influence of additional clonal chromosome abnormalities in Ph negative cells (CCA/Ph(-)) on the efficacy of chronic myeloid leukemia (CML) after tyrosine kinase inhibitors (TKI) treatment. Methods: The clinical data of 28 CML patients with CCA/Ph(-) treated in Henan Cancer Hospital from July 2014 to December 2017 were analyzed retrospectively. The univariate analysis was carried out by Kaplan-Meier method. Multivariate analysis was done by Cox proportional risk model. Results: A total of 28 CCA/Ph(-)patients were recruited including 17 males and 11 females with median age of 42.5 years old. The most common CCA/Ph(-)were trisomy 8 (60.7%), monosomy 7 (14.3%). 64.3% CCA/Ph(-)were transient and 35.7% recurrent (more than 2 times). Cytopenia in two or three lineages of peripheral blood was seen in 42.9% patients. As to the efficacy, 89.3% patients achieved major cytogenetic response (MCyR), 25% with major molecular response (MMR). The median follow-up time was 26.5 months. Treatment failure (TF) of TKI occurred in 32.1% patients with median duration of response 8 (1-41) months. Univariate analysis showed that TF rate was significantly correlated with the frequency of CCA/Ph(-)and cytopenia (all P<0.05). The MMR rate was also significantly correlated with cytopenia (P<0.05). Cytopenia of two lineages or pancytopenia was an independent risk factor related to MMR rate (RR=3.868, 95%CI 1.216-12.298, P=0.022) . Conclusions: Cytopenia in CCA/Ph(-)appears to be an independent risk factor of MMR in CML patients with TKI treatment. The recurrent CCA/Ph(-)may link to higher treatment failure rate. Drug withdrawal or alternative strategy should be considered according to response and the ABL kinase mutations.

Analytical Methodology of Meiosis in Autopolyploid and Allopolyploid Plants.

Meiosis is the cellular process responsible for producing gametes with half the genetic content of the parent cells. Integral parts of the process in most diploid organisms include the recognition, pairing, synapsis, and recombination of homologous chromosomes, which are prerequisites for balanced segregation of half-bivalents during meiosis I. In polyploids, the presence of more than two sets of chromosomes adds to the basic meiotic program of their diploid progenitors the possibility of interactions between more than two chromosomes and the formation of multivalents, which has implications on chromosome segregations and fertility. The mode of how chromosomes behave in meiosis in competitive situations has been the aim of many studies in polyploid species, some of which are considered here. But polyploids are also of interest in the study of meiosis because some of them tolerate the loss of chromosome segments or complete chromosomes as well as the addition of chromosomes from related species. Deletions allow to assess the effect of specific chromosome segments on meiotic behavior. Introgression lines are excellent materials to monitor the behavior of a given chromosome in the genetic background of the recipient species. We focus on this approach here as based on studies carried out in bread wheat, which is commonly used as a model species for meiosis studies. In addition to highlighting the relevance of the use of materials derived from polyploids in the study of meiosis, cytogenetics tools such as fluorescence in situ hybridization and the immunolabeling of proteins interacting with DNA are also emphasized.

Philadelphia-positive case negative for JAK2 V617F mutation with hyperdiploidic karyotype: A case report.

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and accounts for 15-20% of all leukemia cases. The cytogenetic marker of CML is the presence of Philadelphia chromosome (Ph) in >95% of patients. The current case reports a 83-year old woman who was directed to the genetic laboratory for a cytogenetic and molecular-genetic analysis suspected to be Ph positive [(+)]. Karyotype analysis of a bone marrow sample revealed a hyperdiploid karyotype in a part of Ph (+) cells with additional chromosomes 8, 10 and 12. Restriction analysis for V617F JAK2 mutation was negative, while the quantitative RT-qPCR assay indicated BCR-ABL/ABL transcript at the level of 120% International Scale (IS). Generally cytogenetic complexities are important in the prognostic evaluation of CML. Besides the Ph chromosome, a variet of chromosomal aberrations may be associated with CML. A total of 5-10% of these cases show complex translocations involving another chromosome. The current case is Ph(+) demonstrating an additional hyperdiploid karyotype clone with three additional autosomes (8, 10 and 12). This case highlights the significance of cytogenetic abnormalities on the prognosis of CML.

Potential role for second‑generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia harboring additional clonal chromosome abnormalities: A retrospective CML Cooperative Study Group analysis.

Tyrosine kinase inhibitor (TKI) treatment is the standard of care for patients with chronic myeloid leukemia (CML). Even in the imatinib era, the presence of 'clonal chromosomal abnormalities' in the Philadelphia chromosome (CCA/Ph+) at diagnosis reportedly increased the risk of disease progression and predicted shorter survival. However, it remains unclear whether CCA/Ph+ is a poor prognostic marker in the era of new‑generation TKIs. The data of patients with CML in the chronic phase (CP) that were extracted from the CML Cooperative Study Group database were retrospectively analyzed. Of the 328 eligible patients, 33 (10.1%) had CCA/Ph+, including 9 major route and 24 minor route aberrations. The characteristics of patients with and without CCA/Ph+ were similar; however, the proportion of blasts was higher among patients with CCA/Ph+. Notably, the survival rate of patients with CCA/Ph+ was not inferior to that of patients without CCA/Ph+, and there were no differences in responses to TKIs. All 9 patients with major route CCA/Ph+ attained a major molecular response (MMR) with no disease progression, and 8 ultimately achieved a deep molecular response. In particular, the median interval between TKI initiation and achievement of MMR was shorter in patients initially treated with a second‑generation TKI than in those treated with imatinib (5 vs. 10 months). The present retrospective study, thus, revealed favorable treatment outcomes in CML‑CP patients with CCA/Ph+ treated with second‑generation TKIs. The data indicated that administering second‑generation TKIs as first‑line treatments is preferable in CML‑CP patients with CCA/Ph+.

Manejo clínico inicial e implicaciones parentales de la Trisomía 18

Introducción: La trisomía 18 (Síndrome de Edwards), caracterizado por la presencia de un cromosoma adicional en el par 18, es un síndrome relativamente común que afecta aproximadamente a 1 de cada 6.000 nacimientos vivos, es tres veces más frecuente en mujeres que hombres, es una entidad patológica con un mal pronóstico vital.&#x0D; Objetivo: Describir un caso clínico de Trisomía 18 con una evolución desfavorable a pesar de un manejo clínico inicial oportuno a consecuencia de los defectos cardiacos detectados.&#x0D; Material y Métodos: Estudio descriptivo retrospectivo, presentación de caso clínico.&#x0D; Resultados: Se describe la evolución clínica de una recién nacida con rasgos fenotípicos de trisomía 18 confirmada por estudio cromosómico. Siendo una patología cromosómica con múltiples malformaciones asociadas es importante conocerla y tenerlo presente en el diagnóstico diferencial, su detección oportuna nos permitió brindar un adecuado manejo clínico inicial, el mismo que fue insuficiente por la patología cardiaca asociada que produjo un desenlace fatal. La información a los padres con veracidad y simplicidad mejoró su actitud parental frente a la patología de la niña.&#x0D; Conclusión: La detección de defectos congénitos severos en un recién nacido transforma la alegría de su nacimiento en una situación de angustia y tristeza tanto para los padres como para el personal médico. Ante la presencia de defectos congénitos graves asociados, una vez estabilizado el paciente se debe procurar su transferencia a un nivel de atención de mayor complejidad. Dialogar, informar y brindar soporte moral a los padres constituye el primer acto terapéutico de gran significado ético que muchas veces va a ser determinante de la actitud de los padres frente al niño

Comparative meiosis and cytogenomic analysis in euploid and aneuploid hybrids of Urochloa P. Beauv.

The genus Urochloa includes most of the important grasses and hybrids currently used as pastures in the tropical regions. Cytogenetic analyzes have identified some aneuploid hybrids that provide new perspectives for genetic breeding. The objective was to analyze the meiotic behavior in euploid (2n = 4x = 36) and aneuploid (2n = 4x = 36 + 2) hybrids of U. ruziziensis x U. decumbens and U. ruziziensis x U. brizantha. Later, the chromosomes and respective genomes involved in pairing configurations and abnormalities were identified through GISH, with an emphasis on tracking the behavior of the additional chromosomes in the aneuploid hybrid U. ruziziensis x U. decumbens (B1B2B2B2 genomes). The aneuploid U. ruziziensis x U. decumbens shows a higher frequency of univalents, reduction of bivalents, and higher index of irregularities compared with the euploid hybrid. For the aneuploid U. ruziziensis x U. brizantha, there was a reduction in the frequency of univalents, an increase in bivalent and trivalent rates and a lower frequency of abnormalities when compared with the euploid hybrid. The rates of meiotic abnormalities and pairing configurations are parental genotype-dependent and influenced by trisomy. The chromosomes of the B1 and B2 genomes of the aneuploid hybrid (U. ruziziensis x U. decumbens) are involved in the formation of univalents, bivalents, and multivalents in inter-, intra- and inter-intragenomic pairings. In general, the segregation times of chromosomes of the genomes are different, since the chromosomes of the B1 genome segregate more slowly.

A Sequence Resource of Autosomes and Additional Chromosomes in the Peach Pathotype of Alternaria alternata.

Alternaria alternata is a generally saprophytic fungus. Its genome consists of 10 autosomes, while some strains have one or two additional chromosomes, called a conditionally dispensable chromosome (CDC). A CDC is not required for reproduction but confers host-specific pathogenicity. We sequenced the genome of the peach pathotype of A. alternata using Nanopore and assembled it into 20 sequences. The 10 largest sequences corresponded to 10 gapless sequences of A. solani autosomes, and 1 sequence was a mitochondrial genome. Nine other sequences may be derived from CDCs because of lack of similarity with autosomes of other Alternaria spp. The sequence information could provide novel insights into genomes of Alternaria spp. and on the biosynthesis of a novel host-specific toxin in the peach pathotype of A. alternata.

Clinical Retrospective Analysis of Chronic Myeloid Leukemia in Myeloid Blast Crisis

To retrospectively analyze the clinical manifestation, laboratorial test features and prognosis of patients with CML in myeloid blast crisis. The clinical data of 10 patients with CML in myeloid blast crisis admitted in Chinese PLA General Hospital from June 2011 to May 2018 were collected, and their clinical features, laboratorial data and long-term survival were analyzed. The median age of these 10 cases was 32.5 (23-73) years old. Nine cases had chronic phase history. The median chronic phase was 17(4-84) months. All the 10 cases had splenomegaly; B-ultrasonography showed that the median spleen size was 5.2 (4-7.8) cm in thickness, and 14.6 (11.4-19.8) in length. When chronic myeloid leukemia was in blast crisis, the median WBC count was 41.705（11.9-344.41）×109 /L and the median platelet count was 159 (13-2326) ×109 /L. The Ph+ chromosome and BCR-ABL1 fusion gene coulld be detected in all the cases. The chromosome karyotyping showed that additional chromosome abnormalities were found in 5 cases. One case was of low diploid, and two cases were with complex karyotype. ABL1 mutation was detected in 6 out of these 10 cases. ABL1 T315I mutation was detected in 2 of them and one was with deletion of combined P53 in genetic tests. The median follow-up time was 10.5(0.2-78) months. There were 5 cases treated sequentially by chemotheraphy with or without TKI and allo-HSCT. Three cases reached CP2 before transplantation. Among them, two cases still survived without progression for 67 months and 69 months after the transplantation respectively. One case died of transplantation-related mortality (suffered from cerebral hemorrhage 7 months after the transplantation). Two cases were NR before the transplantation, and both died of disease relapse or progression at the time points of one or three months after the transplantation. Five cases treated by TKI ± chemotheraphy and without HSCT succumbed to disease progression. The median time was 6(0.2-22) months. CML patients in myeloid blast crisis treated by chemotheraphy combined with TKI gain CP2, the survival time of patients treated by sequential allo-HSCT is prolonged.

SIGNIFICANCE OF ADDITIONAL CHROMOSOMAL ABNORMALITIES FOR THE OUTCOMES AFTER THE SECOND LINE NILOTINIB THERAPY IN THE CHRONIC MYELOID LEUKEMIA PATIENTS

Background. There is limited information about impact of additional chromosome aberrations (ACA) on the efficacy of the 2nd line nilotinib therapy. Objective. The aim of the study was to analyze significance of ACAs for the outcome after second line tyrosine kinase inhibitors (TKI) therapy with nilotinib in the chronic myeloid leukemia (CML) patients, who experienced previous imatinib therapy failure. Methods. The CML patients in chronic phase treated with nilotinib after imatinib failure were analyzed for outcomes. Results. Among a total of 114 patients, 18 patients (15.8%) had ACAs at the beginning of the 2nd line therapy with nilotinib. Seven patients (38.9%) of 18 had variant translocations and 11 patients (61.1%) had other chromosomal abnormalities in addition to t(9;22), known as clonal evolution. Complete cytogenetic response (CCR) at 12 months was achieved in 37.5%, 42.8% and 45.5% (p=0.842) of patients with classic t(9;22) translocation, variant translocations and ACAs respectively. In the patients with variant translocations t(9;V;22) or clonal evolution treated with nilotinib after the imatinib failure, the CCR and major molecular response (MMR), event free survival (EFS), progression free survival (PFS) and overall survival (OS) rates did not differ from those in the CML patients with t(9;22) only. At the same time quantitative characteristics of leukemic and ACA clones had prognostic value for CCR. The increased number of Ph-positive cells and the number of cells with the ACA at the start of nilotinib therapy reduced the probability of CCR. Conclusions. Higher nilotinib inhibitory activity compare with imatinib allows us to overcome imatinib resistance in the CML patients regardless of the ACA presence at the beginning of nilotinib therapy.

Computational framework for targeted high-coverage sequencing based NIPT.

Non-invasive prenatal testing (NIPT) enables accurate detection of fetal chromosomal trisomies. The majority of publicly available computational methods for sequencing-based NIPT analyses rely on low-coverage whole-genome sequencing (WGS) data and are not applicable for targeted high-coverage sequencing data from cell-free DNA samples. Here, we present a novel computational framework for a targeted high-coverage sequencing-based NIPT analysis. The developed framework uses a hidden Markov model (HMM) in conjunction with a supplemental machine learning model, such as decision tree (DT) or support vector machine (SVM), to detect fetal trisomy and parental origin of additional fetal chromosomes. These models were developed using simulated datasets covering a wide range of biologically relevant scenarios with various chromosomal quantities, parental origins of extra chromosomes, fetal DNA fractions, and sequencing read depths. Developed models were tested on simulated and experimental targeted sequencing datasets. Consequently, we determined the functional feasibility and limitations of each proposed approach and demonstrated that read count-based HMM achieved the best overall classification accuracy of 0.89 for detecting fetal euploidies and trisomies on simulated dataset. Furthermore, we show that by using the DT and SVM on the HMM classification results, it was possible to increase the final trisomy classification accuracy to 0.98 and 0.99, respectively. We demonstrate that read count and allelic ratio-based models can achieve a high accuracy (up to 0.98) for detecting fetal trisomy even if the fetal fraction is as low as 2%. Currently, existing commercial NIPT analysis requires at least 4% of fetal fraction, which can be possibly a challenge in case of early gestational age (<10 weeks) or high maternal body mass index (>35 kg/m2). More accurate detection can be achieved at higher sequencing depth using HMM in conjunction with supplemental models, which significantly improve the trisomy detection especially in borderline scenarios (e.g., very low fetal fraction) and enables to perform NIPT even earlier than 10 weeks of pregnancy.

Genome-wide polymorphisms from RNA sequencing assembly of leaf transcripts facilitate phylogenetic analysis and molecular marker development in wild einkorn wheat.

A survey of genome-wide polymorphisms between closely related species is required to understand the molecular basis of the evolutionary differentiation of their genomes. Two wild diploid wheat species, namely Triticum monococcum ssp. aegilopoides and T. urartu, are closely related and harbour the Am and A genomes, respectively. The A-genome donor of tetraploid and common wheat is T. urartu, and T. monococcum ssp. monococcum is the cultivated form derived from the wild einkorn wheat subspecies aegilopoides. Although subspecies aegilopoides has been a useful genetic resource in wheat breeding, genome-wide molecular markers for this subspecies have not been sufficiently developed. Here, we describe the detection of genome-wide polymorphisms such as single-nucleotide polymorphisms (SNPs) and insertions/deletions (indels) from RNA sequencing (RNA-seq) data of leaf transcripts in 15 accessions of the two diploid wheat species. The SNPs and indels, detected using the A genome of common wheat as the reference genome, covered the entire chromosomes of these species. The polymorphism information facilitated a comparison of the genetic diversity of einkorn wheat with that of two related diploid Aegilops species, namely, Ae. tauschii and Ae. umbellulata. Cleaved amplified polymorphic sequence (CAPS) markers converted from the SNP data were efficiently developed to confirm the addition of aegilopoides subspecies chromosomes to tetraploid wheat in nascent allohexaploid lines with AABBAmAm genomes. In addition, the CAPS markers permitted linkage map construction in mapping populations of aegilopoides subspecies accessions. Therefore, these RNA-seq data provide information for further breeding of closely related species with no reference genome sequence data.

Recurrence of Trisomic Pregnancies in Four Families: A Cytogenetic and Molecular Study

AbstractThe risk for recurrence of non disjunction trisomy 21 is conventionally considered to be less than 1%. Within a span of 3 years, we observed recurrence of non disjunction trisomies in four families. The objective of the present study was to determine low level mosaicism in either of the couple and to identify the parental origin of additional chromosome 21/18. The four couples who had recurrent trisomic conceptions were investigated for the underlying mosaicism by analysis of 100 cells from peripheral blood of the couple and the parental origin of supernumerary chromosome 21/18 were identified using microsatellite markers. Low level mosaicisms in peripheral lymphocytes of couple were ruled out for all four families. Microsatellite markers have shown maternal origin of chromosomal nondisjunction for all the families and defective first meiotic division as the most common mechanism for nondisjunction. This observation raises the need for discussing the option of invasive testing while counseling the couple with an affected child with non-disjunction trisomy as the risk for recurrence of trisomies in subsequent pregnancy might not be as low as 1%.

Molecular cytogenetic characterisation of Elytrigia \xd7mucronata, a natural hybrid of E. intermedia and E. repens (Triticeae, Poaceae)

BackgroundInterspecific hybridisation resulting in polyploidy is one of the major driving forces in plant evolution. Here, we present data from the molecular cytogenetic analysis of three cytotypes of Elytrigia ×mucronata using sequential fluorescence (5S rDNA, 18S rDNA and pSc119.2 probes) and genomic in situ hybridisation (four genomic probes of diploid taxa, i.e., Aegilops, Dasypyrum, Hordeum and Pseudoroegneria).ResultsThe concurrent presence of Hordeum (descended from E. repens) and Dasypyrum + Aegilops (descended from E. intermedia) chromosome sets in all cytotypes of E. ×mucronata confirmed the assumed hybrid origin of the analysed plants. The following different genomic constitutions were observed for E. ×mucronata. Hexaploid plants exhibited three chromosome sets from Pseudoroegneria and one chromosome set each from Aegilops, Hordeum and Dasypyrum. Heptaploid plants harboured the six chromosome sets of the hexaploid plants and an additional Pseudoroegneria chromosome set. Nonaploid cytotypes differed in their genomic constitutions, reflecting different origins through the fusion of reduced and unreduced gametes. The hybridisation patterns of repetitive sequences (5S rDNA, 18S rDNA, and pSc119.2) in E. ×mucronata varied between and within cytotypes. Chromosome alterations that were not identified in the parental species were found in both heptaploid and some nonaploid plants.ConclusionsThe results confirmed that both homoploid hybridisation and heteroploid hybridisation that lead to the coexistence of four different haplomes within single hybrid genomes occur in Elytrigia allopolyploids. The chromosomal alterations observed in both heptaploid and some nonaploid plants indicated that genome restructuring occurs during and/or after the hybrids arose. Moreover, a specific chromosomal translocation detected in one of the nonaploids indicated that it was not a primary hybrid. Therefore, at least some of the hybrids are fertile. Hybridisation in Triticeae allopolyploids clearly and significantly contributes to genomic diversity. Different combinations of parental haplomes coupled with chromosomal alterations may result in the establishment of unique lineages, thus providing raw material for selection.

Effective introgression of wheat D-genome chromosomes into hexaploid triticale (× Triticosecale Wittm.) using trigeneric hybrids

Given the narrow genetic variability of hexaploid triticale, introgressive hybridization is an efficient means to enrich the available genetic pool. The wheat D-genome chromosomes harbor valuable genes for triticale improvement, such as enhancement of biotic and abiotic stress resistance, bread baking quality, and agronomically useful characters. Introducing the wheat D-genome chromosome into triticale may thus improve its agronomic performance and quality. In the present study, we successfully developed the six hexaploid triticale D-genome chromosome introgression lines derived from wheat–rye–Psathyrostachys huashanica trigeneric hybrids. Genomic and fluorescence in situ hybridization (GISH and FISH) karyotyping revealed that K16-4173-3, K16-1565-6, K16-1565-7, and K16-601-1 were 2D(2R), 3D(3B), 3D, 5D(3B, 5R), and 5D(5B) chromosome substitution lines, respectively. K16-4121-3 was found to be a disomic chromosome addition line having a pair of 6D chromosomes. In addition, line K16-1566-4 carried 28 A- and B-genome, 12 R-genome (lacking two 4Rs), two 4D, and two 7D chromosomes. Analysis of these lines using wheat simple sequence repeats (SSRs) and rye specific molecular markers confirmed that corresponding triticale B or R chromosomes had been replaced by D chromosomes of wheat, an observation perfectly consistent with the FISH and GISH results. Furthermore, these lines except for K16-601-1 were highly resistant to the stripe rust pathogen prevalent in China, than Zhongsi828 plants at the adult stages. Our data suggest that the use of trigeneric hybrids as a bridge between triticale and amphiploid wild-wheat forms is an effect strategy for transferring D-genome chromatin into triticale from other breeding programs. The triticale D-genome introgression lines created in this study may serve as new bridging germplasm for hexaploid triticale breeding and should likewise be useful for enhancing triticale genetic diversity.

Genetics and tyrosine kinase inhibitors of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is caused by a reciprocal translocation between 9q34 and 22q11, which produces a chimeric BCR-ABL oncogene located on the Philadelphia chromosome i.e. rearranged 22. The fusion gene implicates in the overexpression of tyrosine kinase through binding with ATP in signal transduction. Therefore, targeted drug development aimed at inhibitors of tyrosine kinase (TKI) and formulated imatinib, which resulted in miraculous disease free survival in majority of the CML patients. However, drug-resistance remained a problem due mainly to emergence of missense point mutations in and around the BCR-ABL kinase domain. Loss of its sensitivity to leukemic stem cells guided development of altered TKIs such as dasatinib, nilotinib, bosutinib and ponatinib—each having specific sensitivity to different amino acid residues (T315I, Y253F/H, E255K/V, M351T, G250E, F359C/V, H396R/P, M244V, E355G, F317L, M237I, Q252H/R, D276G, L248V, F486S), have been implicated in ~ 85% of CML. At chromosomal level, trisomy 8, isochromosome 17q, amplification of the Philadelphia chromosome, additional translocations and complex karyotype are described in TKI-resistant CML. Therefore, mutational events at kinase domain and additional chromosome abnormalities could be considered for development and initiation of TKI-therapy, and cross-talk of complex mutations could lead to formulation of personalized TKI.

Composition and random elimination of paternal chromosomes in a large population of wheat\u2009\xd7\u2009barley (Triticum aestivum L. \xd7 Hordeum vulgare L.) hybrids

Key messageStatistical analysis of the chromosomal composition in a population of 210 primary plants regenerated from two intergeneric wheat–barley cross combinations revealed the random nature of uniparental elimination for barley chromosomes.Uniparental chromosome elimination is a common process in interspecific and intergeneric cereal hybrids. To characterize the frequency of paternal chromosomes, a population of 218 independent green plants was generated from two wheat (♀) × barley (♂) cross combinations via embryo rescue. The chromosomal composition of 210 primary plants was analyzed with chromosome-specific DNA markers representing all seven barley chromosomes. The analysis revealed an equal proportion of haploid and full hybrids (20.5% and 19.5%, respectively), while the rest of the population contained hypoploids (partial hybrids) with no preference for any possible numbers (one to six) of barley chromosome additions. Contrary to the previous reports, there was no statistical bias or preferential elimination for any individual barley chromosome (1H–7H) in this population. The reasons for the apparent contradiction and the implications of the above findings for cereal breeding are discussed.

Clinical Characteristics of Patients with Ph+ Mixed Phenotype Acute Leukemia

To investigate the clinical biological characteristics and prognosis of the patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2) and/or BCRABL1 (Ph+ MPAL). The morphological, immunological, cytogenetic, and molecular features of 33 in patients with Ph+ MPAL were retrospectively analyzed in our center from June 2002 to June 2016 according to the scoring proposal of European Group for the Classification of Acute Leukemia(EGIL )1998 and WHO 2008 criteria. All the cases were either treated with acute lymphoblastic leukemia (ALL) induction regimen or combined chemotherapy regimens for both acute lymphoblastic and acute myeloid leukemia,part of which also received tyrosine kinase inhibitor(TKI) and 5 cases underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after complete remission. Ph+ MPAL occurred predominantly in male patients (ratio of M/F was 1.75∶1), and a high WBC counts at diagnosis; the WBC count was higher than 30×109/L in 25 patients( 75.8% )， and appeared higher than 100 ×109/L in 13 patients ( 39.4%). Among all the 33 Ph+MPAL patients, 32 (97.0%) had a myeloid / B-lymphoid (M/B) phenotype， and 1 case(3.0%) had a myeloid/ B-lymphoid/ T-lymphoid/ (M/B/T) phenotype. There was no patients displayed myeloid / T-lymphoid (M/T) or B-lymphoid/ T-lymphoid/ (B/T) phenotype. 19 of all cases(57.6%) met the diagnosis criteria of Ph+MPAL based on EGIL 1998 criteria, while the remaining 14 cases can be diagnosed as Ph+ MPAL by WHO 2008 classification,but excluded as Ph+MAPL by EGIL 1998.Karyotype analysis was successfully performed in 31 cases, and out of them 13 (41.9%) had a sole Ph chromosome, 10 (32.3%) had additional chromosome aberration and Ph chromosome was not found in 8 cases (25.8%) .In 31 patients the fusion gene BCR/ABL (P190、P210) was detected,including 17 (54.8%) cases with the p190 BCR/ABL transcript, 8 (25.8%) cases with the p210 BCR/ABL transcript, 4 (12.9%) expressing both transcripts and 2 (6.5%) without any one of these 2 transcripts. 24 out of 33 patients (77.4%) achieved complete remission after induction therapy. The median time achieving CR was 43(26-98)days. The CR rate of patients treated with and without imatinib after the first inducion treatment was 81.3% and 46.7%,respectively (P+0.05). Within the 17 patients treated with imatinib at induction stage，2 of which became BCR/ABLnegative．At consolidation chemotherapy stage, 9 out of 16 patients became BCR/ABL negative, including 3 patients already subjected to HSCT. The median time reached to BCR/ABL negative was 2.87（1.13-9.20）months. Ph+ MPAL is more common in male, and inclined to high WBC counts at diagnosis. Myeloid/B lymphoid phenotype is more common, and the prognosis of patients with Ph+MPAL is poor. Imatinib and allogeneic hematopoietic stem cell transplantation may improve survival of patients with Ph+MPAL.

Single Chromosome Aneuploidy Induces Genome-Wide Perturbation of Nuclear Organization and Gene Expression

Chromosomal aneuploidy is a defining feature of carcinomas and results in tumor-entity specific genomic imbalances. For instance, most sporadic colorectal carcinomas carry extra copies of chromosome 7, an aneuploidy that emerges already in premalignant adenomas, and is maintained throughout tumor progression and in derived cell lines. A comprehensive understanding on how chromosomal aneuploidy affects nuclear organization and gene expression, i.e., the nucleome, remains elusive. We now analyzed a cell line established from healthy colon mucosa with a normal karyotype (46,XY) and its isogenic derived cell line that acquired an extra copy of chromosome 7 as its sole anomaly (47,XY,+7). We studied structure/function relationships consequent to aneuploidization using genome-wide chromosome conformation capture (Hi-C), RNA sequencing and protein profiling. The gain of chromosome 7 resulted in an increase of transcript levels of resident genes as well as genome-wide gene and protein expression changes. The Hi-C analysis showed that the extra copy of chromosome 7 is reflected in more interchromosomal contacts between the triploid chromosomes. Chromatin organization changes are observed genome-wide, as determined by changes in A/B compartmentalization and topologically associating domain (TAD) boundaries. Most notably, chromosome 4 shows a profound loss of chromatin organization, and chromosome 14 contains a large A/B compartment switch region, concurrent with resident gene expression changes. No changes to the nuclear position of the additional chromosome 7 territory were observed when measuring distances of chromosome painting probes by interphase FISH. Genome and protein data showed enrichment in signaling pathways crucial for malignant transformation, such as the HGF/MET-axis. We conclude that a specific chromosomal aneuploidy has profound impact on nuclear structure and function, both locally and genome-wide. Our study provides a benchmark for the analysis of cancer nucleomes with complex karyotypes.

Mechanisms of a locally adaptive shift in allocation among growth, reproduction, and herbivore resistance in Mimulus guttatus.

Environmental gradients can drive adaptive evolutionary shifts in plant resource allocation among growth, reproduction, and herbivore resistance. However, few studies have attempted to connect these adaptations to underlying physiological and genetic mechanisms. Here, we evaluate potential mechanisms responsible for a coordinated locally adaptive shift between growth, reproduction, and herbivore defense in the yellow monkeyflower, Mimulus guttatus. Through manipulative laboratory experiments, we found that gibberellin (GA) growth hormones may play a role in the developmental divergence between perennial and annual ecotypes of M. guttatus. Further, we detected an interaction between a locally adaptive chromosomal inversion, DIV1, and GA addition. This finding is consistent with the inversion contributing to the evolutionary divergence between inland annual and coastal perennial ecotypes by reducing GA biosynthesis/activity in perennials. Finally, we found evidence that the DIV1 inversion is partially responsible for a coordinated shift in the divergence of growth, reproduction, and herbivore resistance traits between coastal perennial and inland annual M. guttatus. The inversion has already been established to have a substantial impact on the life-history shift between long-term growth and rapid reproduction. Here, we demonstrate that the DIV1 inversion also has sizable impacts on both the total abundance and composition of phytochemical compounds involved in herbivore resistance.