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Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 2

ABSTRACT: Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. This data is from the lysate fraction of the secretomes described in PXD001476.

INSTRUMENT(S): LTQ FT

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bone Marrow, Bone Marrow Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD003471 | Pride | 2016-02-03

REPOSITORIES: Pride

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Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis.

Wojtuszkiewicz Anna A Schuurhuis Gerrit J GJ Kessler Floortje L FL Piersma Sander R SR Knol Jaco C JC Pham Thang V TV Jansen Gerrit G Musters René J P RJ van Meerloo Johan J Assaraf Yehuda G YG Kaspers Gertjan J L GJ Zweegman Sonja S Cloos Jacqueline J Jimenez Connie R CR

Molecular & cellular proteomics : MCP 20160122 4

Expression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia (AML) blasts at diagnosis is associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. First, we showe ...[more]

PMID: 26801919

Similar Datasets

Human AML secretome and correlation with Anti-Apoptotic Index, part 1

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. Herein, we further explored this aspect of apoptosis in AML. Firstly, the intra-individual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts showed a strong correlation, with expression values far beyond control lymphocytes. Secondly, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p=0.0067 and p=1.0 respectively). Using proteomics we further set out to identify novel proteins possibly engaged in apoptosis regulation. Proteomics analysis revealed that major functional protein clusters upregulated in secretomes of apoptosis-resistant AML, were presumably engaged in global gene regulation including mRNA splicing, protein translation and chromatin remodeling.

2016-02-03 | PXD001476 | Pride

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 3

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-02-03 | PXD001487 | Pride

Single-cell RNA sequencing of erythroid and megakaryocytic acute myeloid leukemia patient cells

Project description:Single-cell RNA sequencing was performed on bone marrow mononuclear of a patient with acute myeloid leukemia with erythroid differentiation of the blasts and on peripheral blood mononuclear cells of a patient with acute myeloid leukemia with megakaryocytic differentiation of the blasts. Raw data for this dataset can be found at the EGA under accession EGAS00001006819.

2022-12-05 | E-MTAB-12607 | biostudies-arrayexpress

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 4

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. The concentrations of these proteins are combined in the Anti Apoptotic index (AAI). We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-02-03 | PXD003478 | Pride

Global Proteomic Profiling of Pediatric AML: A Pilot Study

Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease with several recurrent cytogenetic abnormalities. Despite genomics and transcriptomics profiling efforts to understand AML’s heterogeneity, studies focused on the proteomic profiles associated with pediatric AML cytogenetic features remain limited. Furthermore, the majority of biological functions within cells are operated by proteins (i.e., enzymes) and most drugs target the proteome rather than the genome or transcriptome, thus, highlighting the significance of studying proteomics.

2023-09-26 | PXD043982 | Pride

Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia

Project description:RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML). Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.

2010-07-11 | E-GEOD-16432 | biostudies-arrayexpress

Genome-wide analysis of histone eviction by FAIRE-Seq

Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.

2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress

NF1 inactivation in adult acute myelogenous leukemia

Project description:Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). Conclusions: NF1 null states are present in 7/95=7% of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mTOR-directed therapeutics. Experimental design: We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix SNP 6.0 array-based genomic profiling. 006, 096 and 136 normal Samples have been excluded from study.

2010-12-02 | E-GEOD-21107 | biostudies-arrayexpress

Proteogenomic analysis of relapsed acute myeloid leukemia in adults and children

Project description:Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance determine the major cause of death for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment are yet to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using high resolution isoelectric focusing liquid chromatography mass spectrometry. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

2023-01-09 | PXD031107 | Pride

Expression data from untreated and ATP treated AML blasts

Project description:In the present study, we investigated whether, and to what extent, P2Rs and their ligands are involved in the regulation of AML cells. Our findings show that AML blasts express several receptors belonging to the P2X and P2Y family. Although different samples respond differently to ATP and UTP stimulation (reflecting the variability intrinsic to the group of acute myeloid leukemias), all the tested samples appear to be responsive to purinergic signalling, as demonstrated by intracellular calcium mobilization. GEP analysis demonstrated that ATP induced the expression of cell cycle inhibitors and negative modulators of cell motility, such as inhibitors of GTPase activity. On the contrary, ATP inhibits the expression cell-cycle related genes (cyclins and CDKs), activators of cell motility (Rho GTPases regulators, matrix degradation enzyme and cytoskeleton proteins) and adhesion molecules involved in homing and engraftment. Blast cells obtained from 12 AML patients (3 M0/M1; 3 M2; 3 M4; and 3 M5) were cultured for 24 h with or without 1 mM ATP. Total RNA from 106 ATP-treated and untreated cells was extracted to study variation of gene expression profile induced by ATP treatment in leukemic cells.

2012-02-25 | E-GEOD-30903 | biostudies-arrayexpress

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