scholarly journals Antileukaemic effect of PI3K-mTOR inhibitors in acute myeloid leukaemia-gene expression profiles reveal CDC25B expression as determinate of pharmacological effect

2013 ◽  
Vol 164 (2) ◽  
pp. 200-211 ◽  
Author(s):  
Håkon Reikvam ◽  
Jerome Tamburini ◽  
Silje Skrede ◽  
Rita Holdhus ◽  
Laury Poulain ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mtor Inhibitors ◽  
Pharmacological Effect ◽  
Acute Myeloid

Gene Expression Profiling of Polycomb and Polycomb-Regulated Genes in Patients with Acute Myeloid Leukaemia - Significance and Relationship to Other Molecular Aberrations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3165-3165
Author(s):  
Lykke C. Grubach ◽  
Caroline Juhl-Christensen ◽  
Anita Rethmeier ◽  
Lene H. Olesen ◽  
Peter Hokland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multidrug Resistance ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Expression Profile ◽  
Expression Profiles ◽  
The Other ◽  
Expression Levels ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract The Polycomb group (PcG) of genes is important for differentiation and X-chromosome silencing. Recently much attention has been afforded to the role of its aberrant expression in cancer, especially in relation to the inactivation of tumor suppressor genes. We hypothesized that a deregulation in the expression profile may contribute to the development of acute myeloid leukaemia (AML). To address this, we determined the RNA levels by RQ-PCR in diagnostic bone marrow samples from 126 patients and 20 healthy donors to delineate their expression profile of the PcG genes BMI-1, MEL18, SCML2, YY1 and EZH2. To address the interplay with downstream targets of PcG proteins, we also determined the expression of HOXA4, HOXA9 and MEIS1. These data were compared not only to the demographic and clinical data of the patients, but also to a large number of molecular assays already performed in these patients (Olesen LH et al. Br.J. Haematol. 2005 131(4):457–467; Rethmeier et al. Br.J. Haematol. 2006 133(3):276–283.). At first we noticed a striking heterogeneity in the expression profiles of the AML patients (Fig. 1). We also observed that HOXA9, MEIS1, SCML2, YY1, BMI-1 and EZH2 were significantly (p≤0.003) higher expressed in the patients compared to the healthy donors. Moreover, when patients were analyzed according to the three cytogenetic prognostic groups (normal, core-binding factor positive and complex), the expression profile of patients with the t(8,21) aberration was characterized by a significantly decreased expression of HOXA9 and MEIS1 and a higher one of SCML2, YY1 and BMI-1 than AML patients in general (p<0.003). When evaluating the impact of cytogenetic subgrouping, the expression levels of MEL18 and EZH2 significantly (p< 0.025) reflected highest expression in patients with adverse prognosis and lowest expression with patients exhibiting the most favourable prognosis. While the expression levels of the genes in focus did not correlate to course of disease, we observed that a direct relationship between transcript levels of PcG and PcG-related on the one hand and the DNA methyl transferases (DNMT’s), apoptosis and multidrug-resistance genes (p<0.001) on the other. In conclusion, in this study, which is the first to systematically analyze a series of PcG genes and genes regulated by PcG, we failed to demonstrate a correlation to the clinical outcome of patients with AML. On the other hand, our data strongly suggest that these genes might be involved in the leukaemogenic process by virtue of their relations to DNA methylation (DNMT1, DNMT3B), apoptosis (BAX, CASPASE 3) and multidrug resistance (MDR1, MRP1). Figure 1. Expression profiles of PcG or PcG-regulated genes in AML patients and healthy controls. A. Gene expression profile of all 126 AML patients included (black lines) compared to 20 healthy donors. B. Patients with CBF aberrations, t(8,21), n =7, or inv(16), n =12. The expression is calculated as 2−ΔCt *100), where ΔCt = CtTG−CtCG, CtTG is the Ct value of the target gene, and CtCG is the mean Ct value of the two control genes (B2M and ABL). Figure Figure

scholarly journals ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia

Nature ◽  
2017 ◽  
Vol 543 (7644) ◽  
pp. 265-269 ◽  
Author(s):  
Liling Wan ◽  
Hong Wen ◽  
Yuanyuan Li ◽  
Jie Lyu ◽  
Yuanxin Xi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukaemia ◽  
Histone Acetylation ◽  
Myeloid Leukaemia ◽  
Oncogenic Gene ◽  
Acute Myeloid

Acute Myeloid Leukemia With Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome

2010 ◽  
Vol 28 (4) ◽  
pp. 570-577 ◽  
Author(s):  
Annika Dufour ◽  
Friederike Schneider ◽  
Klaus H. Metzeler ◽  
Eva Hoster ◽  
Stephanie Schneider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Gene Expression Profiles ◽  
Similar Frequency ◽  
Favorable Clinical Outcome ◽  
Acute Myeloid

Purpose CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML). Patients and Methods Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays. Results Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles. Conclusion Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.

Overexpression of BRE in Pediatric MLL-Rearranged Acute Myeloid Leukemia Associated with t(9;11)(p22;q23).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3471-3471
Author(s):  
Brian Balgobind ◽  
C. Michel Zwaan ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
Dirk Reinhardt ◽  
Ursula Creutzig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Apoptotic Effect ◽  
The Mean ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 3471 Poster Board III-359 One important cytogenetic subgroup of pediatric acute myeloid leukemia (AML) is characterized by translocations of chromosome 11q23, which accounts for 15 to 20% of all cases with an evaluable chromosome analysis. In most of these cases, the mixed lineage leukemia (MLL) gene is involved. More than 50 fusion translocation partners of the MLL gene have been identified and outcome differs by translocation partner, suggesting differences in the biological background. So far these biological differences have not been unravelled. Therefore, we investigated the gene expression profiles of MLL-rearranged subgroups in pediatric AML in order to discover and identify the role of differentially expressed genes. Affymetrix Human Genome U133 plus 2.0 microarrays were used to generate gene expression profiles of 257 pediatric AML cases, which included 21 pediatric AML cases with t(9;11)(p22;q23) and 33 with other MLL-rearrangements. With these profiles, we were able to identify a specific gene expression signature for t(9;11)(p22;q23) using an empirical Bayes linear regression model (Bioconductor package: Limma). This signature was mainly determined by overexpression of the BRE (brain and reproductive organ-expressed) gene. The mean average VSN normalized expression for BRE in the t(9;11)(p22;q23) subgroup was 3.7-fold higher compared with that in other MLL-rearranged cases (p<0.001). Validation by RQ-PCR confirmed this higher expression in t(9;11)(p22;q23) cases (p<0.001). In addition, we confirmed that overexpression of BRE was predominantly found in t(9;11)(p22;q23) in an independent gene expression profile cohort (Ross et al, Blood 2002). Remarkably, MLL-rearranged cases with a BRE expression higher than the mean expression showed a significant better 3 year disease free survival than MLL-rearranged cases with a lower expression (80±13% vs. 30±10%, p=0.02). Previously, overexpression of BRE has been described in hepatocellular carcinomas (HCC) (Chang et al., Oncogene 2008) and an anti-apoptotic effect was described. We transfected BRE in the monomac-1 cell line, which harbors a t(9;11)(p22;q23). We did not find a proliferative advantage for BRE overexpression using a BrDU-assay nor changes in drug sensitivity, indicating that the anti-apoptotic effect as described for HCC in vivo could not be confirmed in vitro in AML. In conclusion, overexpression of the BRE gene is predominantly involved in pediatric MLL-rearranged AML with t(9;11)(p22;q23). Moreover, high expression of BRE showed a favorable prognosis. We did not find any influence of BRE expression on cell proliferation or apoptosis in vitro. This indicates that further studies involving the role of the MLL-fusion protein on BRE transcription are necessary to unravel the leukemogenic role in pediatric AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression

Blood ◽  
2009 ◽  
Vol 114 (23) ◽  
pp. 4847-4858 ◽  
Author(s):  
Kunju Sridhar ◽  
Douglas T. Ross ◽  
Robert Tibshirani ◽  
Atul J. Butte ◽  
Peter L. Greenberg
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Differential Gene Expression ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Differential Gene ◽  
Acute Myeloid

AbstractMicroarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene “poor risk” signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.

scholarly journals Gene expression profiles in acute myeloid leukemia with common translocations using SAGE

2006 ◽  
Vol 103 (4) ◽  
pp. 1030-1035 ◽  
Author(s):  
S. Lee ◽  
J. Chen ◽  
G. Zhou ◽  
R. Z. Shi ◽  
G. G. Bouffard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Acute Myeloid
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