Prognostic gene signature for AML
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE37642 | GEO | 2013/02/07
SECONDARY ACCESSION(S): PRJNA162567
REPOSITORIES: GEO
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Project description:Acute myeloid leukemia (AML) is a heterogeneous disease in respect of molecular aberrations and prognosis. We used gene expression profiling of 562 patients treated in the German AMLCG 1999 trial to develop a gene signature that predicts survival in AML. Analysis of 562 samples (140 HGU-133plus2; 422 HGU-133A; 422 HGU-133B) from adult patients with acute myeloid leukemia (AML).
2013-02-07 | E-GEOD-37642 | biostudies-arrayexpress
Project description:Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Keywords: clinical outcome
2008-08-22 | GSE12417 | GEO
Project description:Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Experiment Overall Design: Analysis of 163 samples of bone morrow or peripheral blood mononuclear cells from adult patients with untreated acute myeloid leukemia
2008-10-26 | E-GEOD-12417 | biostudies-arrayexpress
Project description:PURPOSE: Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. PATIENTS AND METHODS: To define a VPA in vitro response signature we profiled gene expression in myeloid leukemia cell lines (HL60, NB4, HEL, and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age<60yrs) and within the AMLSG 06-04 trial for older adults (age>60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA. cDNA microarrays from the Stanford Functional Genomics Facility were used to perform mRNA transcript profiling of 4 leukemia cell lines treated with 1mM VPA for 48 hours in comparison to untreated cell lines, and to perform mRNA transcript profiling of freshly-frozen, from matched acute myeloid leukemia peripheral blood specimens collected from 14 AML patients at diagnosis and following 48 hours of treatment with either chemotherapy +/- VPA.
2012-09-19 | E-GEOD-32240 | biostudies-arrayexpress
Project description:Relapse in acute myeloid leukemia (AML) may result from variable genetic origins or convergence on common biological processes. Exploiting the specificity and sensitivity of regulatory DNA, we analyze patient samples of multiple clinical outcomes covering various AML molecular subtypes. We uncover regulatory variation between patients translating into a transcriptional signature that predicts relapse risk. In addition, we find clusters of co-expressed genes within this signature selectively link to relapse risk in distinct patient subgroups defined by molecular subtype or AML maturation. Analyzing these gene clusters and the AML subtypes separately enhances their prognostic value substantially and provides insight in the mechanisms underlying relapse risk across the distinct patient subgroups. We propose that prognostic gene expression signatures in AML are valid only within patient subgroups and do not transcend these subgroups.
2019-09-10 | GSE117994 | GEO
Project description:PURPOSE: Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. PATIENTS AND METHODS: To define a VPA in vitro response signature we profiled gene expression in myeloid leukemia cell lines (HL60, NB4, HEL, and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age<60yrs) and within the AMLSG 06-04 trial for older adults (age>60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA.
2012-09-19 | GSE32240 | GEO
Project description:Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. In addition, this data set has also been used to identify a common prognostic gene signature in human AML (Li Z. et al., unpublished). 93 human AML samples bearing various cytogenetic and molecular abnormalities are used to identify miR-181 target genes and a common prognostic gene signature.
2012-04-03 | E-GEOD-30285 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis and cell-cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged M-bM-^IM-%60 years) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. We analyzed 148 older cytogenetically normal(CN)-AML patients samples using a custom microarray platform and describe the expression of lncRNAs among the AML samples.
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Project description:Acute myeloid leukemia (AML) is the most common and severe acute leukemia in adults. It is a heterogeneous disease where the subset of molecularly different types, presenting various morphological features and differentiation stage, can be distinguished. Genomic research of leukemias is conducted since 1999 and large cohort studies shown that particular genetic alterations correspond with specific gene expression signatures. However, not always they provide clinically relevant information. The most unknown group is cytogenetically normal acute myeloid leukemia (CN-AML, 40-49% of all AML cases). The aim of our experiment was to determine selected gene expression profiles in CN-AML, using small, boutique microarray. The array contained 933 oligonucleotide probes, mainly complementary to acute myeloid leukemia markers, genes involved in leukemic transformation and myeloid cell proliferation, differentiation and maturation. Our test dataset included 40 hybridizations: 24 corresponding with blood and bone marrow samples collected from 12 patients with AML M1 or M2 FAB subtype and 16 corresponding with healthy control samples. Total RNA was extracted from the mononuclear cell fractions, reversibly transcribed to cDNA and labeled with Alexa 647 dye. The common reference was RNA isolated from HL-60 cell culture, labeled with Alexa 555 dye.
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