Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptional profiling of Acute Myeloid Leukaemia (AML) cells following co-culture with anti-CD44. RNA-seq of anti-CD44 treated, paired, attached, detached and cells in monoculture using two AML cell lines, KG1a and OCI-AML3

ABSTRACT: Although 80% of AML patients can initially achieve a complete remission, the long-term disease-free survival is only 40% at 6 years with a 10% 5-year survival rate from first relapse. Most patients do not achieve a second remission. Therefore, relapse after initial response to chemotherapy remains a serious clinical challenge requiring new therapeutic strategies. Annual relapse rates have been calculated 40%, 17%, and 2% in years 1-3, respectively. One of the issues hindering the successful treatment of AML patients, and contributing to disease relapse, is leukaemic cell adhesion and retention in the protective niche of the BMME. Here, the leukaemic cells are surrounded by other cell types that promote their survival, by enabling them to evade destruction by both the immune system and intra-vascular therapies, ultimately leading to the emergence of drug resistance. Given the dependence of AML cells on the BMME, a better understanding of the biological interactions between the leukaemic cells and the haematopoietic niche is needed. In addition, the identification and development of therapies to target these adhesive interactions will enable AML cells to be forced out of their BMME protective niche, into the peripheral circulation, where they will be more susceptible to conventional drug regimens. We have developed and optimised a robust, reproducible, in vitro co-culture model of the AML-BMME. Using the optimised model, several adhesion blocking agents were tested to reduce the number of adhered AML cells. Anti-CD44 treatment was established as the most effective in preventing AML adhesion of OCI-AML3, KG1a and primary AML cells. However, even with maximum dose of the most promising blocking agent, some AML cells still adhered. Following this observation, KG1a and OCI-AML3 cells were treated in co-culture and monoculture. Subsequently paired adhered, non-adhered and monoculture cells were isolated and sent for RNA sequencing in order to perform comparative transcriptomic analysis. The results from these experiments helped us identify novel targets from the persistently adhered AML cells in order to more effectively block their adhesion on our model.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Eleni Ladikou

PROVIDER: E-MTAB-14052 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia.

Ladikou Eleni E EE Chevassut Timothy T Pepper Chris J CJ Pepper Andrea Gs AG

British journal of haematology 20200305 5

Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build-up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated w ...[more]

PMID: 32135579

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Project description:Surface expression of C-X-C chemokine receptor type 4 (CXCR4) in acute myeloid leukemia (AML) has been reported to be an independent prognostic factor for disease relapse and survival. We previously reported that targeting the stromal-derived factor 1M-NM-1 (SDF-1M-NM-1)/CXCR4 axis could overcome resistance of AML cells to chemotherapy both in vitro and in vivo. To further explore the mechanism of targeting CXCR4, in the current study we focused on the regulation of microRNA. Microarray analysis revealed that the hsa-let-7a microRNA was down-regulated in OCI-AML3 cells by SDF-1M-NM-1 treatment and increased after CXCR4 inhibition. To further investigate the role of hsa-let-7a in leukemia biology, we overexpressed it in AML cell lines, which resulted in decreased Bcl-xL protein expression and consequently enhanced cell sensitivity to the chemotherapeutic agent cytarabine, both in vitro and in vivo. We also identified the transcription factor Yin Yang 1 (YY1) as a mediator that links the SDF-1M-NM-1/CXCR4 axis with hsa-let-7a. Western blotting and immunocytochemistry demonstrated a correlation between YY1 and CXCR4 activation. ChIP assay confirmed the binding of YY1 to pri-let-7a DNA fragments. In primary AML samples (n=50), high CXCR4 surface expression was associated with low hsa-let-7a levels (r2=0.53). Improved effects of cytarabine treatment associated with greatly extended survival of human AML carrying mice was observed in primary human AML overexpressing hsa-let-7a. On the basis of these results, we propose that CXCR4 regulation of hsa-let-7a microRNA through YY1 and transcriptional silencing of the Bcl-xL protein together identifies a novel mechanism by which CXCR4 functions to induce chemoresistance in AML cells. MicroRNA expression profiling of OCI-AML3 cell lines treated with CXCR4 antagonist or SDF-1M-NM-1. OCI-AML3 cells were treated with 100 ng/mL SDF-1M-NM-1 or 250 nM POL6326 (a CXCR4 antagonist, Allschwil, Switzerland), total RNA was extracted at specific time points (1, 2, 4, and 8 h), and miRNA expression profiling was performed

Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.

Dataset Information

Transcriptional profiling of Acute Myeloid Leukaemia (AML) cells following co-culture with anti-CD44. RNA-seq of anti-CD44 treated, paired, attached, detached and cells in monoculture using two AML cell lines, KG1a and OCI-AML3

Publications

Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia.

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