The zebrafish reference genome sequence and its relationship to the human genome.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies.

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

cDNA synthesis for BCR-ABL1 detection at the MMR level: the importance of using the appropriate kit.

BACKGROUND: The synthesis of complementary DNA (cDNA) for use in the detection of BCR-ABL1 at the Major Molecular Response (MMR) level is a well-established method used by clinical laboratories world-wide. However, the quality of cDNA provides sensitivity challenges and consequently affects the detection of Minimal Residual Disease (MRD). RESULTS: Herein, we evaluated six commercially available kits for the synthesis of cDNA according to amplification success rate, linearity and ABL1 copy number. Based on our results, the Invitrogen SuperScript® III Reverse Transcriptase kit performed better, among the ones used in this study, for the cDNA synthesis, followed by the First Strand cDNA Synthesis Kit for RT-PCR (AMV), available from Roche Applied Sciences. CONCLUSIONS: Accurate and sensitive testing for the detection of abnormal transcripts, allows the correct stratification and treatment of patients. Hence, the use of a suitable kit for the cDNA synthesis is of great importance. This study provides a comprehensive point of reference for clinical laboratories in an attempt to optimize BCR-ABL1 detection. We propose that the Invitrogen SuperScript® III Reverse Transcriptase kit is the most suitable, among the ones used in this study, for the cDNA synthesis to be used for the detection of BCR-ABL1 at the MMR level in a CML MRD assay.

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol.

Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients.

Calreticulin mutations in myeloproliferative neoplasms and new methodology for their detection and monitoring.

The diagnosis of the BCR-ABL-negative myeloproliferative neoplasms (MPN), namely polycythemia vera, essential thombocythemia and primary myelofibrosis has relied significantly on the detection of known causative mutations in the JAK2 or MPL genes, which account for the majority of MPN patients. However, around 30 % of patients with MPN, primarily essential thombocythemia and primary myelofibrosis, lack mutations in these two genes making it difficult to reach a confident diagnosis in these cases. The recent discovery of frameshift mutations in CALR in approximately 70 % of MPN patients lacking the JAK2 and MPL mutations offers a reliable diagnostic marker for the latter group. A review of the current literature, plus unpublished data from our laboratory, shows that 55 different CALR insertion/deletion mutations have been identified so far in MPN patients. Among these 55 variants reported to date, a 52-base pair deletion and a 5-base pair insertion are by far the most prominent representing 50 and 35 %, respectively, of all cases with CALR mutations. In this paper, we describe a high-resolution melting (HRM) analysis and a Taqman® Real-Time PCR (RQ-PCR) assay and we propose a new clinical laboratory diagnostic algorithm for CALR mutation analysis. According to this algorithm, samples can go through front-line screening with HMR or fragment analysis, followed by the newly developed RQ-PCR to both discriminate and quantify the two most common mutations in CALR gene.

Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

Fecal Microbiota and Associated Volatile Organic Compounds Distinguishing No-Adenoma from High-Risk Colon Adenoma Adults.

Microbiota and the metabolites they produce within the large intestine interact with the host epithelia under the influence of a range of host-derived metabolic, immune, and homeostatic factors. This complex host-microbe interaction affects intestinal tumorigenesis, but established microbial or metabolite profiles predicting colorectal cancer (CRC) risk are missing. Here, we aimed to identify fecal bacteria, volatile organic compounds (VOC), and their associations that distinguish healthy (non-adenoma, NA) from CRC prone (high-risk adenoma, HRA) individuals. Analyzing fecal samples obtained from 117 participants ≥15 days past routine colonoscopy, we highlight the higher abundance of Proteobacteria and Parabacteroides distasonis, and the lower abundance of Lachnospiraceae species, Roseburia faecis, Blautia luti, Fusicatenibacter saccharivorans, Eubacterium rectale, and Phascolarctobacterium faecium in the samples of HRA individuals. Volatolomic analysis of samples from 28 participants revealed a higher concentration of five compounds in the feces of HRA individuals, isobutyric acid, methyl butyrate, methyl propionate, 2-hexanone, and 2-pentanone. We used binomial logistic regression modeling, revealing 68 and 96 fecal bacteria-VOC associations at the family and genus level, respectively, that distinguish NA from HRA endpoints. For example, isobutyric acid associations with Lachnospiraceae incertae sedis and Bacteroides genera exhibit positive and negative regression lines for NA and HRA endpoints, respectively. However, the same chemical associates with Coprococcus and Colinsella genera exhibit the reverse regression line trends. Thus, fecal microbiota and VOC profiles and their associations in NA versus HRA individuals indicate the significance of multiple levels of analysis towards the identification of testable CRC risk biomarkers.

MicroRNA expression in Sezary syndrome: identification, function, and diagnostic potential.

MicroRNAs are commonly aberrantly expressed in many cancers. Very little is known of their role in T-cell lymphoma, however. We therefore elucidated the complete miRNome of purified T cells from 21 patients diagnosed with Sézary Syndrome (SzS), a rare aggressive primary cutaneous T-cell (CD4(+)) lymphoma. Unsupervised cluster analysis of microarray data revealed that the microRNA expression profile was distinct from CD4(+) T-cell controls and B-cell lymphomas. The majority (104 of 114) of SzS-associated microRNAs (P < .05) were down-regulated and their expression pattern was largely consistent with previously reported genomic copy number abnormalities and were found to be highly enriched (P < .001) for aberrantly expressed target genes. Levels of miR-223 distinguished SzS samples (n = 32) from healthy controls (n = 19) and patients with mycosis fungoides (n = 11) in more than 90% of samples. Furthermore, we demonstrate that the down-regulation of intronically encoded miR-342 plays a role in the pathogenesis of SzS by inhibiting apoptosis, and describe a novel mechanism of regulation for this microRNA via binding of miR-199a* to its host gene. We also provide the first in vivo evidence for down-regulation of the miR-17-92 cluster in malignancy and demonstrate that ectopic miR-17-5p expression increases apoptosis and decreases cell proliferation in SzS cells.

A de novo SFMBT1 pathogenic variant identified in a boy with Poland syndrome.

Poland syndrome is a rare developmental disorder characterized by unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, accompanied with ipsilateral hand malformations. To date, no clear genetic cause has been associated with Poland syndrome, although familial cases have been reported. We report the employment of trio exome investigation and the identification of a heterozygous de novo pathogenic variant in the SFMBT1 gene, a transcription factor associated with transcriptional repression during development, in a 14-yr-old boy with Poland syndrome. We further demonstrate by means of cDNA sequencing and western blot analysis that this variant results in SFMBT1 exon 10 skipping and a lower concentration of the SFMBT1 wild-type protein. To our knowledge, the heterozygous pathogenic SFMBT1 variant identified in association with this condition is novel as it has not been elsewhere described in the literature and it can be incorporated to the limited reported cases published.

Clinical values of gene alterations as marker of minimal residual disease in non-M3 acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system. Residual leukemic cells after treatment are associated with relapse. Thus, detecting minimal residual disease (MRD) is significant. Major techniques for MRD assessment include multiparameter flow cytometry (MFC), polymerase chain reaction (PCR), and next-generation sequencing (NGS). At a molecular level, AML is the consequence of collaboration of several gene alterations. Some of these gene alterations can also be used as MRD markers to evaluate the level of residual leukemic cells by PCR and NGS. However, when as MRD markers, different gene alterations have different clinical values. This paper aims to summarize the characteristics of various MRD markers, so as to better predict the clinical outcome of AML patients and guide the treatment.

Network Pharmacology and Experimental Validation Reveal the Effects of Chidamide Combined With Aspirin on Acute Myeloid Leukemia-Myelodysplastic Syndrome Cells Through PI3K/AKT Pathway.

Chidamide (CDM), a novel histone deacetylase inhibitor, is currently used for patients with peripheral T-cell lymphoma. Aspirin (ASA), an anti-inflammatory drug, has been shown to exert anticancer activity. Herein, we investigated the effect of CDM combined with ASA on myelodysplastic syndromes-derived acute myeloid leukemia (AML-MDS) cells and explored the underlying mechanism. The putative targets of CDM and ASA were predicted by network pharmacology approach. GO functional and KEGG pathway enrichment analyses were performed by DAVID. Furthermore, experimental validation was conducted by Cell Counting Kit-8 assay, Flow cytometry and Western blotting. Network pharmacology analysis revealed 36 AML-MDS-related overlapping genes that were targets of CDM and ASA, while 10 hub genes were identified by the plug-in cytoHubba in Cytoscape. Pathway enrichment analysis indicated CDM and ASA significantly affected PI3K/AKT signaling pathway. Functional experiments demonstrated that the combination of CDM and ASA had a remarkable synergistic anti-proliferative effect by blocking the cell cycle in G0/G1 phase and inducing apoptosis. Mechanistically, the combination treatment significantly down-regulated the phosphorylation levels of PI3K and AKT. In addition, insulin-like growth factor 1 (IGF-1), an activator of PI3K/AKT pathway, reversed the effects of the combination treatment. Our findings suggested that CDM combined with ASA exerted a synergetic inhibitory effect on cell growth by inactivating PI3K/AKT pathway, which might pave the way for effective treatments of AML-MDS.

Racial/Ethnic Disparities on the Risk of Second Malignant Neoplasm Among Hodgkin Lymphoma Survivors.

BACKGROUND: Hodgkin lymphoma survivors are at risk for second malignant neoplasm (SMN). How race/ethnicity affects the risk remains unclear. METHODS: This retrospective cohort study included 22,415 patients diagnosed with primary Hodgkin lymphoma from January 1992 to December 2015 in 13 Surveillance, Epidemiology, and End Results-based registries and divided patients into four groups: non-Hispanic whites, non-Hispanic blacks, Hispanics, and Asian/others. Taking non-Hispanic whites as a reference, both the proportional subdistribution hazard (PSH) and the cause-specific hazard (CSH) methods were used to calculate the SMN hazard ratio for other racial/ethnic groups with and without considering the competing mortality risk. RESULTS: 1,778 patients developed SMN with a median follow-up of 11.63 years. In the adjusted PSH model, Hispanic, Asian/others, and non-Hispanic black patients had 26% (PSH, 0.74; 95% CI, 0.63-0.87), 20% (PSH, 0.80; 95% CI, 0.64-1.01), and 12% (PSH, 0.88; 95% CI, 0.75-1.03) decreased overall SMN hazard, respectively. Moreover, the PSH method revealed the racial/ethnic difference in the SMN risk in the skin, the respiratory system, and the endocrine system. These hazards were slightly higher and different with the use of the CSH approach. In addition to the aforementioned overall SMN and subtypes, adjusted CSH analysis also revealed the racial/ethnic disparities in the risk of subsequent female breast cancer, digestive cancer, and non-Hodgkin lymphoma. CONCLUSIONS: The subtype and SMN risk among Hodgkin lymphoma survivors varied by race/ethnicity. The use of CSH and PSH provides a dynamic view of racial/ethnic effects on SMN risk in Hodgkin lymphoma survivors.

Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells.

FOXP2 mutation causes a severe inherited speech and language defect, while the related transcription factors FOXP1, FOXP3 and FOXP4 are implicated in cancer. FOXP2 mRNA and protein expression were characterised in normal human tissues, haematological cell lines and multiple myeloma (MM) patients' samples. FOXP2 mRNA and protein were absent in mononuclear cells from different anatomical sites, lineages and stages of differentiation. However, FOXP2 mRNA and protein was detected in several lymphoma (8/20) and all MM-derived cell lines (n = 4). FOXP2 mRNA was expressed in bone marrow samples from 96% of MM patients (24/25), 66.7% of patients with the pre-neoplastic plasma cell proliferation monoclonal gammopathy of undetermined significance (MGUS) (6/9), but not in reactive plasma cells. The frequency of FOXP2 protein expression in CD138(+) plasma cells was significantly higher in MGUS (P = 0.0005; mean 46.4%) and MM patients (P < or = 0.0001; mean 57.3%) than in reactive marrows (mean 2.5%). FOXP2 (>10% nuclear positivity) was detectable in 90.2% of MM (55/61) and 90.9% of MGUS (10/11) patients, showing more frequent expression than CD56 and labelling 75% of CD56-negative MM (9/12). FOXP2 represents the first transcription factor whose expression consistently differentiates normal and abnormal plasma cells and FOXP2 target genes are implicated in MM pathogenesis.

HSPG2 overexpression independently predicts poor survival in patients with acute myeloid leukemia.

Heparan sulfate proteoglycan 2 (HSPG2), also known as perlecan, is a large multi-domain extracellular matrix proteoglycan, which contributes to the invasion, metastasis and angiogenesis of solid tumor. However, very little is known about the effect of HSPG2 on acute myeloid leukemia (AML). This study aims to investigate the prognostic value of the HSPG2 gene in terms of overall survival and leukemia-free survival in patients with AML. Bone marrow mononuclear cells (BMMCs) from 4 AML patients and 3 healthy controls were processed for RNA-Sequencing (RNA-seq). The mRNA expression level of HSPG2 in BMMCs and CD34+ hematopoietic stem/progenitor cells (HSPC) obtained from enrolled participants and human leukemic cell lines was detected by RT-qPCR. Then the correlations between the expression of HSPG2 and a variety of important clinical parameters, such as median white blood cell (WBC) count and bone marrow (BM) blasts, were further analyzed. The expression level of HSPG2 was significantly upregulated in AML patients at the time of diagnosis, downregulated after complete remission and then elevated again at relapse. Moreover, HSPG2 expression was associated with median WBC count (P < 0.001), median hemoglobin (P = 0.02), median platelet count (P = 0.001), and BM blasts (P < 0.001) in AML patients. Patients with high HSPG2 expression had both worse overall survival (OS) (P = 0.001) and poorer leukemia-free survival (LFS) (P = 0.047). In the multivariate analysis model, HSPG2 was identified as an independent prognostic biomarker of AML. Taken together, these results indicate that HSPG2 overexpression was associated with poor prognosis in AML patients, and may be a prognostic biomarker and therapeutic target of AML.

Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma.

MicroRNAs are naturally occurring small RNA species that regulate gene expression and are frequently abnormally expressed in cancers. However, the role of microRNAs in lymphoma is poorly understood. Therefore, we undertook a comprehensive study of microRNA expression in two of the most common lymphomas: diffuse large B-cell lymphoma (DLBCL) (n = 80) and follicular lymphoma (FCL) (n = 18) using microarrays containing probes for 464 human microRNAs. Unsupervised cluster analysis revealed distinct expression patterns between these two lymphomas and specific microRNA signatures (including members of the miR-17-92 cluster) were derived that correctly predicted lymphoma type in >95% of cases. Furthermore, we identified microRNAs in de novo DLBCL (n = 64) associated with germinal centre-like and non-germinal centre-like immunophenotypes, international prognostic index status and event-free survival in CHOP and rituximab (R)-CHOP treated patients. Despite the indolent nature of FCL a significant proportion of cases undergo high-grade transformation to more aggressive DLBCL. In order to see if transformation is associated with changes in microRNA expression we compared transformed DLBCL cases (n = 16) with de novo DLBCL, as well as FCL cases that underwent subsequent transformation (n = 7) with FCL cases that had not transformed at a median follow-up of 60 months (n = 11). Differential expression of 12 microRNAs correctly predicted >85% of transformed versus de novo DLBCL cases; six microRNAs (miR-223, 217, 222, 221 and let-7i and 7b) were found which could similarly predict or transformation in FCL (P < 0.05). These data suggest that microRNAs have potential as diagnostic and prognostic markers in these lymphomas and may be used to identify FCL patients at risk of high-grade transformation.

MicroRNA­143 increases cell apoptosis in myelodysplastic syndrome through the Fas/FasL pathway both in vitro and in vivo.

Whilst the role of microRNA­143 (miR­143) in myelodysplastic syndrome (MDS) remains unclear, abnormally expressed microRNA­143 has been detected in many types of cancer tissues. In this study, we describe a cohort study for the verification of miR­143 expression, as well as the investigation of the molecular mechanisms of miR­143 in MDS/acute myeloid leukaemia (AML). In a series of experiments, miR­143 recombinant lentiviral vectors transformed into SKM­1 cells were either overexpressed or knocked down, and the results illustrated that the overexpression of miR­143 inhibited SKM­1 cell growth, arrested the SKM­1 cells in the G0/G1 phase, interfered with cell proliferation and induced cell apoptosis via the Fas/FasL pathway. Conversely, miR­143 knockdown induced a decrease in the apoptosis and promoted the proliferation of SKM­1 cells. Moreover, miR­143 was shown to suppress MLLT3/AF9 expression by binding to its 3'­UTR. Taken together, the findings of this study indicate that miR­143 may be a critical regulator of MDS/AML cell carcinogenesis, acting as a potent antitumour molecular target for the diagnosis or treatment of cancers associated with the abnormal expression of MLLT3/AF9, hence facilitating the development of potential therapeutics against MDS/AML.

Definition of the zebrafish genome using flow cytometry and cytogenetic mapping.

BACKGROUND: The zebrafish (Danio rerio) is an important vertebrate model organism system for biomedical research. The syntenic conservation between the zebrafish and human genome allows one to investigate the function of human genes using the zebrafish model. To facilitate analysis of the zebrafish genome, genetic maps have been constructed and sequence annotation of a reference zebrafish genome is ongoing. However, the duplicative nature of teleost genomes, including the zebrafish, complicates accurate assembly and annotation of a representative genome sequence. Cytogenetic approaches provide "anchors" that can be integrated with accumulating genomic data. RESULTS: Here, we cytogenetically define the zebrafish genome by first estimating the size of each linkage group (LG) chromosome using flow cytometry, followed by the cytogenetic mapping of 575 bacterial artificial chromosome (BAC) clones onto metaphase chromosomes. Of the 575 BAC clones, 544 clones localized to apparently unique chromosomal locations. 93.8% of these clones were assigned to a specific LG chromosome location using fluorescence in situ hybridization (FISH) and compared to the LG chromosome assignment reported in the zebrafish genome databases. Thirty-one BAC clones localized to multiple chromosomal locations in several different hybridization patterns. From these data, a refined second generation probe panel for each LG chromosome was also constructed. CONCLUSION: The chromosomal mapping of the 575 large-insert DNA clones allows for these clones to be integrated into existing zebrafish mapping data. An accurately annotated zebrafish reference genome serves as a valuable resource for investigating the molecular basis of human diseases using zebrafish mutant models.

Deregulated microRNA expression and its pathogenetic implications for myelodysplastic syndromes.

OBJECTIVE: Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal hematological stem cell disorders characterized by ineffective hematopoiesis, cytopenias. MicroRNAs (miRNAs) are short non-coding RNA molecules that repress gene expression at the post-transcriptional level. In this review, we summarize advanced investigations that underscore deregulated miRNA expression in MDS, and discuss the implications of miRNAs in the molecular pathogenesis of MDS. METHODS: Relevant English-language literatures were searched and retrieved from PubMed using the terms MDS and miRNAs. RESULTS: The majority of studies have focused on profiling miRNA expression in MDS, only a small number of studies have investigated the exact pathogenic role of miRNAs in MDS. DISCUSSION: In the hematopoietic system, miRNAs are critical regulators of the differentiation of hematopoietic stem/progenitor cells. Thus, it is not surprising that dysregulation of miRNAs can lead to hematopoietic stem cell anomalies and further cause MDS. Deregulated miRNA expression has been identified in MDS, and it contributes to the pathogenesis and progression of MDS. Chromosomal aberrations, hypermethylation of miRNA promoters, and mutations of miRNA genes may lead to dysregulation of miRNA in MDS. However, the complex regulatory networks between miRNAs and their potential target genes in MDS still need to be explored in further studies. CONCLUSIONS: Although the function of miRNAs is not fully understood, these small non-coding RNAs represent novel pathogenetic and clinical implications in MDS. The studies of miRNAs may guide us towards a better understanding of this disease and shed light on the development of new therapeutic strategies.

miR-378 inhibits cell growth and enhances apoptosis in human myelodysplastic syndromes.

miR-378 has been proven to inhibit cell growth, migration and invasion in different types of cancers. In this study, we found that miR-378 was commonly downregulated in the bone marrow cells obtained from myelodysplastic syndrome (MDS) patients. We further investigated the role of miR-378 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the leukemic phase during the progression of MDS to AML (MDS/AML). Results indicated that overexpression of miR-378 in SKM-1 cells interfered with proliferation via inducing apoptosis and G0/G1-phase cell cycle arrest, and suppressive effect of miR-378 on MDS/AML cells may be mediated partly through Bcl-w and CDC40. Moreover, apoptosis induced by miR-378 correlated with increased expression of Bax and activation of caspase-3, -8 and -9. Taken together, our data support a critical role for miR-378 in the pathogenesis of MDS and provide a novel therapeutic target in this complex disease.

Molecular mechanisms of the progression of myelodysplastic syndrome to secondary acute myeloid leukaemia and implication for therapy.

Myelodysplastic syndrome (MDS) includes a heterogeneous group of clonal haematological stem cell disorders characterized by dysplasia, cytopenias, ineffective haematopoiesis, and an increased risk of progression to acute myeloid leukaemia (AML), which is also called secondary AML (sAML). Approximately one-third of patients with MDS will progress to sAML within a few months to a few years, and this type of transformation is more common and rapid in patients with high-risk MDS (HR-MDS). However, the precise mechanisms underlying the evolution of MDS to sAML remain unclear. Currently, chemotherapy for sAML has minimal efficacy. The only method of curing patients with sAML is allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Unfortunately, only a few patients are appropriate for transplantation because this disease primarily affects older adult patients. Additionally, compared to de novo AML, sAML is more difficult to cure, and the prognosis is often worse. Therefore, it is important to clarify the molecular mechanisms of the progression of MDS to sAML and to explore the potent drugs for clinical use. This review will highlight several molecular mechanisms of the progression of MDS to sAML and new therapeutic strategies of this disease.