Project description:Genome wide DNA methylation profiling of blood and bone marrow of Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia. The Illumina Infinium EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across over 860,000 CpGs.
Project description:tRNA related fragments(tRF) and tRNA halves(tiRNA) are novel class of short non-coding RNA derived from tRNAs. Using RNA sequencing, we evaluated the tRFs/tiRNAs expression profiles in relapsed/refractory multiple myeloma and multiple myeloma patients. Bioinformatics analyses indicated that tRFs/tiRNAs may be involved in the progression and drug-resistance of multiple myeloma.
Project description:Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapies of these patients. A new oral histone deacetylase inhibitor, chidamide shows anti-tumor activity by activating the pro-apoptosis pathway in some other hematological malignancies, suggesting its potential application to the relapsed and refractory B cell lymphoma. In this study, we examined the therapeutic effects of chidamide on the cell and mouse models of the rituximab/chemotherapy resistant B cell lymphoma, as well as the primary B cell lymphoma cells. In Raji-4RH and RL-4RH cells, the rituximab/chemotherapy resistant B cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest, which were associated with E2F1/2 inactivation and CDK2 degradation. The primary B cell lymphoma cells from Rituximab/chemotherapy relapsed and refractory patients were also very sensitive to chidamide treatment. Interestingly, chidamide triggered the cell death via the autophagy pathway instead of the activation of apoptosis in Raji-4RH and RL-4RH cells, likely due to the lack of the pro-apoptotic proteins in these resistant cells. In the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as the direct target genes of chidamide, which control the autophagy and cell cycle respectively in RRCL treated with chidamide. Moreover, the combination of chidamide with the chemotherapy drug Cisplatin sensitized the RRCL to growth inhibition in a synergistic manner. Chidamide-Cisplatin combination significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, our studies provides a theoretic and mechanistic basis for further evaluation of the chidamide-based clinical trial for rituximab/chemotherapy relapsed and refractory B cell lymphoma patients.
Project description:Reversing gene expression signatures in relapsed patient may restore chemosensitivity. We demonstrate that the histone deacetylase inhibitor vorinostat not only reprograms the aberrant gene expression profile of relapsed blasts but is synergistic when applied prior to chemotherapy in primary patient samples and leukemia cell lines
Project description:Reversing gene expression signatures in relapsed patient may restore chemosensitivity. We demonstrate that the histone deacetylase inhibitor vorinostat not only reprograms the aberrant gene expression profile of relapsed blasts but is synergistic when applied prior to chemotherapy in primary patient samples and leukemia cell lines Primary patient samples were collected from patients treated at the New York University Medical Center and from the Childrenâs Oncology Group (COG) cell bank,RNA was isolated from three primary patient samples and three B-lineage leukemia cell lines with or without treatment with vorinostat for 24 hours.
Project description:Purpose: In childhood acute lymphoblastic leukemia (ALL), approximately 25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors, i. e. time and site of relapse, immunophenotype and minimal residual disease. However, the underlying biological determinants of these prognostic factors remain poorly understood. Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared to late relapsed disease. The vast majority of genes was up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G/2M phase cells and this correlated well with the expression level of cell cycle genes. Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis. Experiment Overall Design: We performed gene expression profiling on 60 prospectively collected samples of children with first relapse of acute lymphoblastic leukemia enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Muenster study group.
Project description:Frequent inactivating mutations of histone acetyltransferase CREBBP is a characteristic feature of diffuse large B-cell lymphoma (DLBCL), highlighting the attractiveness of targeting the CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor as most patients exhibit resistance, hampering the clinical utility of the drug. Functional studies in both in vitro and in vivo models showed that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulating cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibited G2/M transition during cell cycling, as top candidates that synergistically enhanced antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrated that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while a combination of AURKA inhibitor and chidamide provides a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.