Feasibility Study of Switching to Nilotinib After First-line Imatinib in the Chronic Phase of Chronic Myeloid Leukemia.

BACKGROUND: We investigated the real-life choice of first-line treatment in the chronic phase of chronic myeloid leukemia (CML-CP) and the feasibility of switching to nilotinib after first-line imatinib. PATIENTS AND METHODS: We performed a retrospective analysis of the efficacy and safety of imatinib versus nilotinib as first-line therapy for patients with CML-CP. We also performed a comparative analysis of the efficacy of sustained imatinib versus a switch to nilotinib for patients with CML-CP with a warning or failure response or intolerance to imatinib. We also comparatively analyzed the efficacy between first-line nilotinib and first-line imatinib after standardized management in accordance with the European Leukemia Network (ELN) recommendations. A total of 344 patients were included in the present study. RESULTS: The proportion of patients achieving a complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4.0 (MR4.0) was greater with first-line nilotinib than with first-line imatinib at 0 to 24 and 0 to 36 months (P < .05). Of the 344 patients, 174 did not achieve an optimal response to first-line imatinib. A greater proportion of those patients who had switch to nilotinib had achieved a CCyR, MMR, and MR4.0 compared with those continuing imatinib for 12 months of subsequent treatment (P < .005). No difference was found in the proportion of patients with a CCyR, MMR, and MR4.0 between first-line nilotinib and first-line imatinib after standardized management in accordance with the ELN recommendations at 0 to 24 and 0 to 36 months (P > .05). CONCLUSION: First-line imatinib can result in efficacy similar to that with first-line nilotinib after standardized management in accordance with the ELN recommendations. Treatment with imatinib as first-line treatment, with a switch to nilotinib after standardized management is feasible and effective.

SMRT sequencing analysis reveals the full-length transcripts and alternative splicing patterns in Ananas comosus var. bracteatus.

BACKGROUND: Ananas comosus var. bracteatus is an herbaceous perennial monocot cultivated as an ornamental plant for its chimeric leaves. Because of its genomic complexity, and because no genomic information is available in the public GenBank database, the complete structure of the mRNA transcript is unclear and there are limited molecular mechanism studies for Ananas comosus var. bracteatus. METHODS: Three size fractionated full-length cDNA libraries (1-2 kb, 2-3 kb, and 3-6 kb) were constructed and subsequently sequenced in five single-molecule real-time (SMRT) cells (2 cells, 2 cells, and 1 cell, respectively). RESULTS: In total, 19,838 transcripts were identified for alternative splicing (AS) analysis. Among them, 19,185 (96.7%) transcripts were functionally annotated. A total of 9,921 genes were identified by mapping the non-redundant isoforms to the reference genome. A total of 10,649 AS events were identified, the majority of which were intron retention events. The alternatively spliced genes had functions in the basic metabolism processes of the plant such as carbon metabolism, amino acid biosynthesis, and glycolysis. Fourteen genes related to chlorophyll biosynthesis were identified as having AS events. The distribution of the splicing sites and the percentage of conventional and non-canonical AS sites of the genes categorized in pathways related to the albino leaf phenotype (ko00860, ko00195, ko00196, and ko00710) varied greatly. The present results showed that there were 8,316 genes carrying at least one poly (A) site, which generated 21,873 poly (A) sites. These findings indicated that the quality of the gene structure and functional information of the obtained genome was greatly improved, which may facilitate further genetic study of Ananas comosus var. bracteatus.

Screening and characterization of long noncoding RNAs involved in the albinism of Ananas comosus var. bracteatus leaves.

Long noncoding RNAs (lncRNAs) have been reported to play key regulatory roles in plant growth, development, and biotic and abiotic stress physiology. Revealing the mechanism of lncRNA regulation in the albino portions of leaves is important for understanding the development of chimeric leaves in Ananas comosus var. bracteatus. In this study, a total of 3,543 candidate lncRNAs were identified, among which 1,451 were differentially expressed between completely green (CGr) and completely white (CWh) leaves. LncRNAs tend to have shorter transcripts, lower expression levels, and greater expression specificity than protein-coding genes. Predicted lncRNA targets were functionally annotated by the Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A lncRNA-mRNA interaction network was constructed, and 36 target mRNAs related to chlorophyll metabolism were predicted to interact with 86 lncRNAs. Among these, 25 significantly differentially expressed lncRNAs putatively interacted with 16 target mRNAs. Based on an expression pattern analysis of the lncRNAs and their target mRNAs, the lncRNAs targeting magnesium chelatase subunit H (ChlH), protochlorophyllide oxidoreductase (POR), and heme o synthase (COX10) were suggested as key regulators of chlorophyll metabolism. This study provides the first lncRNA database for A. comosus var. bracteatus and contributes greatly to understanding the mechanism of epigenetic regulation of leaf albinism.

Comparative transcriptomic and proteomic analyses of the green and white parts of chimeric leaves in Ananas comosus var. bracteatus.

BACKGROUND: Ananas comosus var. bracteatus has high ornamental value due to its chimeric leaves. However, the chimeric trait is very unstable in red pineapple plants, and transcriptional variation between the two types of cells (white/green cells) and the molecular mechanism responsible for their albino phenotype remain poorly understood. METHODS: Comparative transcriptomic and proteomic analyses of the white parts (Whs) and green parts (Grs) of chimeric leaves were performed. RESULTS: In total, 1,685 differentially expressed genes (DEGs) (712 upregulated and 973 downregulated) and 1,813 differentially abundant proteins (DAPs) (1,018 with low abundance and 795 with high abundance) were identified. Based on Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the DEGs were mostly involved in carbon fixation in photosynthetic organisms, porphyrin and chlorophyll metabolism and oxidative phosphorylation, while proteomic analysis revealed that DAPs were mostly related to ribosomes, photosynthesis, photosynthesis antennas, and porphyrin and chlorophyll metabolism. Combined analysis showed increased mRNA levels but low abundance of nine proteins level in Whs /Grs related to photosynthetic pigment and photosynthesis. Transcriptional changes, posttranscriptional regulation and translational alterations of key enzymes involved in chlorophyll biosynthesis and photosynthesis may play important roles in the albino parts of chimeric leaves.

High-throughput sequencing analysis revealed the regulation patterns of small RNAs on the development of A. comosus var. bracteatus leaves.

Studies of the molecular mechanisms involved in the formation of the albino leaf cells are important for understanding the development of chimera leaves in Ananas comosus var. bracteatus. In this study, we identified a total of 163 novel miRNAs involved in the development of complete white (CWh) and complete green (CGr) leaves using high-throughput sequencing method. The potential miRNA target genes were predicted and annotated using the NR, Swiss-Prot, GO, COG, KEGG, KOG and Pfam databases. The main biological processes regulated by miRNAs were revealed. The miRNAs which potentially play important roles in the development of the leaves and the albino of the CWh leaf cells were selected and their expression patterns were analyzed. The expression levels of nine miRNAs and their potential target genes were studied using qRT-PCR. These results will help to elucidate the functional and regulatory roles of miRNAs in the formation of the albino cells and the development of the leaves of A. comosus var. bracteatus. These data may also be helpful as a resource for studies of small RNA in other leaf color chimeric plant species.