Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA144051 | ENA |
REPOSITORIES: ENA
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Project description:AML with mutated NPM1 usually carries normal karyotype (NK) but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93/631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1). NPM1-mutated AML with NK or AK showed overlapping morphological, immunophenotypic (CD34-negativity) and gene expression profile (downregulation of CD34 and upregulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a normal or abnormal karyotype, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype. All bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.
2009-06-01 | E-GEOD-16015 | biostudies-arrayexpress
Project description:Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. Leukemia associated antigens (LAA) might be suitable structures to be attacked by immunotherapeutic agents. We performed primary AML sample enrichment and microarray studies to define LAA expression levels in AML. We compared the LAA expression in the enriched CD34+CD38- AML fraction to that of enriched HSC of healthy donors and AML bulk cells (CD34+CD38+, CD34-CD38+ and CD34-CD38). Furthermore, we investigated the expression patterns of co-stimulatory molecules in LSC, bulk AML cells and enriched HSC, Conclusion: We demonstrated the differential expression of several LAA in LSC, and their suitability as target structures. We enriched primary AML samples using CD34 and CD38 as markers to compare LAA expression levels of LSC, HSC and AML bulk. LAA expression profiles comparing LSC, HSC and leukemic bulk AML citation: Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens Vanessa Schneider, Lu Zhang, Markus Rojewski, Natalie Fekete, Hubert Schrezenmeier, Alexander Erle, Lars Bullinger, Susanne Hofmann, Marlies Götz, Konstanze Döhner, Susann Ihme, Hartmut Döhner, Christian Buske, Michaela Feuring-Buske, Jochen Greiner
2015-04-23 | E-GEOD-68172 | biostudies-arrayexpress
Project description:Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. Leukemia associated antigens (LAA) might be suitable structures to be attacked by immunotherapeutic agents. We performed primary AML sample enrichment and microarray studies to define LAA expression levels in AML. We compared the LAA expression in the enriched CD34+CD38- AML fraction to that of enriched HSC of healthy donors and AML bulk cells (CD34+CD38+, CD34-CD38+ and CD34-CD38). Furthermore, we investigated the expression patterns of co-stimulatory molecules in LSC, bulk AML cells and enriched HSC, Conclusion: We demonstrated the differential expression of several LAA in LSC, and their suitability as target structures. We enriched primary AML samples using CD34 and CD38 as markers to compare LAA expression levels of LSC, HSC and AML bulk.
2015-04-23 | GSE68172 | GEO
Project description:10 to 30% normal karyotype acute myeloid leukemia (AML) patients express mutations in regulators of DNA methylation such as TET2 or DNMT3A in conjunction with activating mutation in receptor tyrosine kinase, FLT3, which can be present in up to 50% of normal karyotype AML patients. These patients have poor prognosis since they do not respond well to established therapies. Here, utilizing mouse models of AML that recapitulate cardinal features of the human disease and bear a combination of loss of function mutations in either Tet2 or Dnmt3a along with expression of Flt3ITD, we show that inhibition of SHP2, a protein tyrosine phosphatase, essential for cytokine receptor signaling, including FLT3, by a small molecule allosteric inhibitor, SHP099, impairs growth and induces differentiation of leukemic cells without impacting normal hematopoietic cells. We further show that SHP099 normalizes gene expression program associated with increased cell proliferation and self-renewal in leukemic cells by down regulating the Myc signature. Our results provide a new and more effective target for treating a subset of AML patients bearing a combination of genetic and epigenetic mutations.
2019-07-26 | GSE134843 | GEO
Project description:AML with mutated NPM1 usually carries normal karyotype (NK) but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93/631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1). NPM1-mutated AML with NK or AK showed overlapping morphological, immunophenotypic (CD34-negativity) and gene expression profile (downregulation of CD34 and upregulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a normal or abnormal karyotype, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype.
2009-06-01 | GSE16015 | GEO
Project description:A leukemia cell fraction highly enriched for LSCs was generated in a mouse model of AML induced by co-expression of MLL target genes Hoxa9 and Meis1. Limit dilution transplantation analyses performed on various prospectively isolated leukemia cell subpopulations revealed that cells capable of transplanting AML to syngeneic recipient mice (the operational definition of LSCs) were highly enriched in the leukemia cell fraction displaying an immunophenotype (Lin- Sca1- c-kit+ CD16/32+ CD34+) comparable to normal GMPs, referred to as L-GMPs. For the purpose of identifying genes that are differentially expressed in LSCs, microarray expression profiling was performed on L-GMPs (from leukemic mice) and GMPs (from normal mouse BM) purified by flow cytometry.
2015-10-02 | GSE64773 | GEO
Project description:Mononuclear cells from AML patients (n=46) were sorted into CD34+ and CD34- subfractions and genome-wide expression analysis was performed using Illumina BeadChip Arrays (HT12 v3). Of 2 AML samples only the CD34+ fraction could be analyzed. AML CD34+ and CD34- gene expression was compared to a large group of normal CD34+ bone marrow cells (n=31).
2011-07-19 | GSE30029 | GEO
Project description:Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34CD38_ cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34CD38_ cell fraction from AML and compared their gene expression profiles to the CD34CD38 cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy. Microarrays were used to compare the gene expression patterns between AML CD34+CD38- cells and AML CD34+CD38+
2011-12-01 | E-GEOD-34044 | biostudies-arrayexpress
Project description:We applied a novel approach of parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations from patients with acute myeloid leukemia (AML) and a normal karyotype. We isolated phenotypic long-term HSC (LT-HSC), short-term HSC (ST-HSC), and committed granulocyte-monocyte progenitors (GMP) from individual patients, and measured gene expression profiles of each population, and in comparison to their phenotypic counterparts from age-matched healthy controls. Bone marrow samples from AML patients with normal karyotype and age-matched healthy controls were used in this study. Hematopoietic stem and progenitor compartments were purified by multiparameter-high speed fluorescence-activated cell sorting (FACS) from CD34+ enriched bone marrow to isolate LT-HSC (Lin-/CD34+/CD38-/CD90+), ST-HSC (Lin-/CD34+/CD38-/CD90-), and GMP (Lin-/CD34+/CD38+/CD123+/CD45R+).
2012-09-05 | E-GEOD-35008 | biostudies-arrayexpress
Project description:More than 40% of patients with AML have a normal karyotype and are included in the intermediate prognostic group, in which risk classification is currently poor defined and more molecular markers are needed to achieve treatment stratification. EVI1 overexpression (OE) has been reported to discriminate in this group those with a worse prognosis. The EVI1 mice homolog has a role in the HSC proliferation through Gata2 expression, therefore, GATA2, a transcription factor with a relevant role in hematopoiesis, could be a candidate gene in the leukemogenic transformation in AML in patients with normal karyotype, and in other subgroups. GATA2 OE was detected in 46% of cases with normal karyotype, and was more frequent among samples with FLT3-ITD (p=0.0021), especially among the AML-M1 cases. We found a mutational pattern FLT3-ITD/GATA2-OE/WT1-OE that could define a subgroup of patients with normal karyotype and AML-M1, with a different gene expression array pattern and a poor prognosis. Our results show that GATA2 OE is a common event in AML cases with normal karyotype (46%). The deregulation of the expression of the GATA2 transcription factor would lead to a hematopoietic differentiation impairs, focusing GATA2 as a candidate gene that fits in the cooperating model for the multistep pathogenesis that causes AML transformation. Keywords: Disease state analysis
2005-10-27 | GSE3505 | GEO