Comparison of Clinical and Biologic Significance of WT1 Mutations in Populations of Older (≥60 years[y]) and Younger (<60 y) Adult Patients (Pts) with Cytogenetically Normal (CN) De Novo Acute Myeloid Leukemia (AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 326-326
Author(s):  
Heiko Becker ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Age Groups ◽  
Stem Cell Marker ◽  
Treatment Intensity ◽  
Prognostic Impact ◽  
Wild Type ◽  
Age Related ◽  
Exon 9 ◽  
Wt1 Mutation

Abstract Abstract 326 Mutations of the Wilms tumor (WT1) gene are found in ∼10% of younger (<60 years[y]) adult pts with de novo CN-AML and impact adversely on their outcome. The clinical significance of WT1 mutations has not yet been evaluated in older (≥60 y) CN-AML pts. Therefore, we analyzed frequency and clinical impact of WT1 mutations in the context of other molecular markers in a relatively large cohort of 243 pts ≥60 y (range, 60-83 y) with de novo CN-AML treated intensively on upfront cytarabine/daunorubicin-based CALGB protocols. Included pts were those with material available for analysis of WT1 mutation status and that of a panel of other validated molecular prognosticators including NPM1, FLT3 (ie, FLT3-ITD, FLT3-TKD) and CEBPA mutations, BAALC and ERG expression levels. Mutations in WT1 “hot spots” (exons 7 and 9) were assessed by DHPLC and sequencing. The results were compared with the findings in younger (18-59 y) CALGB pts (n=207) characterized molecularly in a similar fashion. Gene expression profiles in both populations were assessed centrally using Affymetrix U133 plus 2.0 microchip. Among the 243 older pts, 16 (7%) had WT1 mutations. Of those, 14 had single WT1 mutations in exon 7 [frameshift (n=8), nonsense (n=1), and missense (n=1)] or in exon 9 [missense (n=4)]; 1 pt had 2 frameshift mutations in exon 7, and 1 had 1 frameshift mutation in exon 7 and 1 missense mutation in exon 9. Compared with older WT1 wild-type pts, older WT1 mutated pts more often had FLT3-ITD (P<.001) and had lower hemoglobin (P=.01), and higher WBC (P=.03) and % blood blasts (P=.03). WT1 mutated pts had a trend for lower complete remission (CR) rates (50% v 70%, P=.16) and shorter OS (P=.08; Figure 1), but similar disease-free survival (DFS; P=.59; Figure 2) compared with WT1 wild-type pts. The frequency of WT1 mutations tended to be lower in older than younger pts (7% v 12%, P=.07). Mutation types and pretreatment clinical and molecular characteristics associated with WT1 mutations were similar between the two age groups. Despite differences in treatment intensity, there were no significant differences in younger v older WT1 mutated pts with regard to CR rates (P=.18), or OS (P=.68; Figure 1) or DFS (P=.66; Figure 2) durations. In contrast, younger WT1 wild-type pts had significantly higher CR rates (P<.001), and longer OS (P<.001; Figure 1) and DFS (P<.001; Figure 2) than older WT1 wild-type pts. Although associated with WT1 mutations in both the younger (P=.02) and older age groups, FLT3-ITD had no impact on CR rates (P=.28), or OS (P=.15) or DFS (P=.21) durations of all WT1 mutated pts after controlling for age-related treatment intensity. To provide insights into the molecular features associated with WT1 mutations we analyzed the whole cohort (younger and older) for genes differentially expressed (ie, P≤.001) between WT1 mutated and WT1 wild-type pts. A signature comprising 110 named genes was derived. Among the 71 upregulated genes in WT1 mutated pts, were those encoding the leukemia stem cell marker CD96 and the leukemia fusion protein partners PML and MLL. The most upregulated gene (6.2 fold) was GTSF1, which, like WT1, may be involved in germ cell development. Among the 39 genes downregulated in WT1 mutated pts, were those encoding SNRPN and SNURF, involved in pre-mRNA processing, and the insulin receptor and IRS2, upstream effectors of the PI3K/AKT pathway. In conclusion, WT1 mutations in older CN-AML pts are less frequent than in younger pts. While WT1 mutations independently associate with shorter OS and DFS in younger CN-AML pts, in older CN-AML pts they are only associated with trends for a worse CR rate and shorter OS. This difference appears due to the poor outcome of the older compared to younger WT1 wild-type pts, which reduced the prognostic impact of WT1 mutations in the former. Nevertheless, the outcome of pts with WT1 mutations is equally poor in older and younger pts regardless of differences in treatment, thereby suggesting that WT1 mutated CN-AML may constitute a distinct biologic entity across age groups. The unique gene expression signature associated with WT1 mutations could provide useful insights into WT1 mutation-driven leukemogenic mechanisms across age-related groups, and help in devising novel molecular targeted therapeutic approaches for this subtype of CN-AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1611
Author(s):  
Nur Fathiah Abdul Abdul Sani ◽  
Ahmad Imran Zaydi Amir Amir Hamzah ◽  
Zulzikry Hafiz Abu Abu Bakar ◽  
Yasmin Anum Mohd Mohd Yusof ◽  
Suzana Makpol ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Cognitive Aging ◽  
Successful Aging ◽  
Expression Patterns ◽  
Age Groups ◽  
Genetic Network ◽  
Cross Sectional ◽  
Age Related ◽  
Age Related Cognitive Decline

The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult’s susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.

Analysis of ASXL1, IDH1, IDH2, c-CBL, and WT1 Mutations in De Novo Acute Myeloid Leukaemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1450-1450
Author(s):  
Mariam Ibañez ◽  
Esperanza Such ◽  
Jose Cervera ◽  
Irene Luna ◽  
Sandra Dolz ◽  
...  
Keyword(s):  
De Novo ◽  
Prognostic Impact ◽  
Significant Implication ◽  
Wild Type ◽  
Idh Mutations ◽  
Flt3 Mutations ◽  
Exon 4 ◽  
De Novo Aml ◽  
Cebpa Mutations ◽  
Acute Myeloid

Abstract Abstract 1450 The clinical relevance and prognostic implications of some recently identified mutations in acute myeloid leukemia (AML) is not yet well established. Among them, we have selected to be analyzed those affecting the following genes: Additional Sex Combs-Like 1 (ASXL1), Isocitrate Dehydrogenase (IDH1 and IDH2), Casitas B-lineage Lymphoma (c-CBL), and Wilms Tumor 1 (WT1). They have been previously reported with a variable incidence: ASXL1 mutations in 10.8% patients with normal karyotype (NK), IDH1 and IDH2 mutations in 8 – 33% of de novo AML, c-CBL mutations in 2% of de novo AML, and WT1 mutations in 5–12% of de novo AML patients. In order to know the incidence and prognostic impact of these mutations and their possible cooperative role in leukemogenesis, we have screened for ASXL1, IDH1, IDH2, c-CBL, WT1, FLT3, NPM1 and CEBPa, mutations in a cohort of de novo AML patients from a single centre. We studied 174 de novo AML patients [98M/76F; median age: 62 yr. (range: 16 – 88); favourable (n= 13), intermediate (n= 86) and high (n= 51) cytogenetic risk classification by the MRC group]. DNA was isolated from bone marrow samples obtained at diagnosis. In order to determine cooperating mutations, we developed a new combination of high-resolution melting (HRM) assays on a LightCycler® 480 and lastly direct sequencing, to detect somatic mutations for ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), WT1 (exons 7, 8 and 9) and c-CBL (exons 8 and 9). All mutations reported in this study were confirmed al least twice. FLT3 (ITD and D835Y), NPM1 (exon 12) and CEBPa were performed as described previously by standard methods. Sequence analysis was checked by its corresponding GeneBank Accession Number. The number of patients found to carry mutations in our series was: 16 patients with ASXL1 mutations (9.2%), 16 patients with IDH mutations (2.9% had a IDH1R132, 12.6% the SNP rs11554137 and 6.3% IDH2R140), 5 patients with WT1 mutations (2.9%), 37 patients with FLT3 mutations (21.3%), 44 patients with NPM1 mutations (25,3%) and 8 patients with CEBPa mutations (4.6%). No mutations where found in c-CBL. We could not found a pattern of cooperating mutations in the studied group of genes. WT1, FLT3 and NPM1 were associated with leukocyte count >30 × 109/L at diagnosis (80% vs. 31% for WT1, P =0,022; 68% vs. 22% for FLT3, P= 0.001; and 50% vs. 24% for NPM1, P= 0.002; in mutated vs. wild-type patients, respectively). WT1 was also associated with a platelet count > 50 × 109/L at diagnosis (100% vs. 57% in mutated vs. wild-type patients, respectively; P =0,048). Besides, FLT3 and NPM1 mutations were more frequent in the intermediate cytogenetic risk group (82% and 74%; P =0.004 and P =0.047; respectively). ASXL1 and IDH mutations were not correlated with any of the clinical and biological features studied. In univariate analysis, only age and cytogenetics had an impact on overall survival (OS, median of 12mo vs. 3mo, for patients < and ≥65 yr., P <0.001 and 24mo, 11mo and 3mo for favourable, intermediate and high risk, P =0.005). Mutational status of ASXL1, IDH1, IDH2, WT1, FLT3, NPM1 and CEBPa did not impact on outcome in the whole series. However, when the analysis was restricted to patients with intermediate cytogenetic risk, patients with FLT3 mutations had a shorter OS (19mo vs. 8mo, wild-type vs. mutated patients; P =0.047) and those with WT1 mutations showed a trend towards an inferior OS (11mo vs. 1mo, wild-type vs. mutated patients; P = 0.066). In multivariate analysis in patients with intermediate cytogenetic risk, the age [HR (95% CI) = 3.3 (1.9 − 5.9) P <0.001], and FLT3 status [HR (95% CI) = 2.2 (1.2–3.9) P =0.008] retained an independent adverse significance for OS. In terms of relapse free survival any of the variables showed a significant implication. To sum up, the incidence found for the studied genes was lower than the previously reported: ASXL1, 9.2%; IDH1R132, 2.9%; IDH2R140, 6.3%; WT1, 2.9%; and c-CBL, 0%. We were unable to find a pattern of cooperating mutations in the studied group of genes or any impact of these mutations on the outcome. Disclosures: No relevant conflicts of interest to declare.

Adverse Prognostic Impact of GAS6 Expression in De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (CALGB 8461, 9665, 20202; Alliance)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1293-1293
Author(s):  
Susan Whitman ◽  
Jessica Kohlschmidt ◽  
Kati Maharry ◽  
Deedra Nicolet ◽  
Sebastian Schwind ◽  
...  
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
White Blood Count ◽  
Categorical Variables ◽  
Prognostic Impact ◽  
Age Group ◽  
Wild Type ◽  
Aberrant Expression ◽  
Expression Status

Abstract Abstract 1293 Receptor tyrosine kinases (RTKs) constitutively activated by gene mutation, overexpression and/or autocrine activation via ligand expression have been shown to negatively impact on outcomes of AML patients (pts). AXL, a member of the TAM (TYRO3, AXL, MERTK) RTK gene family was reported to be overexpressed and associated with poor survival in AML (Rochlitz, et al, Leukemia, 1999: 13:1352–8). No AXL mutations have been described, suggesting its activation may occur via aberrant expression in leukemic blasts of a TAM RTK ligand, GAS6. GAS6 was shown to be overexpressed in AML (Dirks, et al Leuk. Res. 23:643–51); yet its prognostic relevance is unknown. We report clinical and molecular associations and prognostic impact of aberrant GAS6 expression, in the context of TAM RTKs and known prognostic markers in de novo CN-AML pts (n=270; aged 18–83 y) treated with cytarabine/anthracycline-based therapies. Sixty-nine (26%) pts expressed GAS6 (>background signal; derived from microarray gene expression profiles of AML samples). TYRO3 expression status [positive (+) vs negative (–)] was similar in GAS6+ and GAS6– pts (P=.74), while AXL+ (P<.001) and low expression MERTK (P=.02) were more frequent in GAS6+ pts. Compared to GAS6– pts, GAS6+ pts were older (P=.02), had more platelets (P=.03), lower % blood blasts (P=.01) and increased frequency of hepatomegaly (P=.006); were more often NPM1 (P<.001) and CEBPA (P=.02) wild-type, and RUNX1 (P<.001) and ASXL1 (P=.002) mutated and expressed higher MN1 levels (P=.05). In univariable analyses, none of the TAM RTKs associated with complete remission (CR) and only TYRO3+ associated with reduced disease-free (DFS; P=.005), overall (OS; P=.005) and event-free survival (EFS; P=.008). GAS6+ vs GAS6– pts had lower CR rates (P<.001), shorter DFS (P=.03), OS (P=.004) and EFS (P<.001). While no TAM RTK entered the CR multivariable (MVA) model, GAS6+ expression status remained an independent marker for lower CR rate after adjusting for NPM1 status, white blood count (WBC) and age group (Table). In the DFS, OS and EFS models (Table), there was an interaction between GAS6 and the combined dual receptor (TYRO3/AXL) variable. GAS6 independently associated with shorter survival in TYRO3–/AXL– pts but not TYRO3+/AXL+ pts after adjusting for other variables. We show for the 1st time that GAS6 expression is an independent prognostic marker in CN-AML; negatively impacting on CR attainment, independent of TAM RTKs and on survival endpoints in pts lacking TYRO3 and AXL expression, regardless of MERTK expression. Our results suggest that GAS6 expressed by AML blasts plays a role in chemotherapy resistance. As GAS6 is expressed but not its RTKs in a subgroup of pts with poor outcome, this may lead to the hypothesis that the prognostic impact of GAS6 in those patients is mediated by the encoded ligand acting on cells other than AML blasts including, for example, natural killer cells, where activation of AXL RTK is reported to suppress innate immunity. Table. MVA models Variable CR DFS OS EFS P OR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) GAS6 expression, + v – .02 0.46 (0.24, 0.88) .03* 1.78 (1.07, 2.96) .05* 1.59 (1.00, 2.52) .03* 1.59 (1.06, 2.41) NPM1, mut v wt .001 2.97 (1.53, 5.77) – – – – .006 0.64 (0.46, 0.88) FLT3-ITD, present v absent – – .003 1.66 (1.19, 2.33) – – .005 1.55 (1.14, 2.11) WT1, mut v wt – – – – <.001 3.42 (1.97, 5.96) .03 1.84 (1.06, 3.18) RUNX1, mut v wt – – – – .002 2.00 (1.29, 3.10) – – ASXL1, mut v wt – – – – – – .003 1.66 (1.05, 2.60) DNMT3A
 R882 mut v wt
 Non-R882 v wt .006 .21 1.65 (1.15, 2.36) 1.33 (0.85, 2.08) WBC, continuous, 50 unit increase <.001 0.56 (0.41, 0.76) – – – – <.001 1.25 (1.12, 1.39) Age group, ≥ 60 y v < 60 y .01 0.40 (0.19, 0.83) <.001 2.09 (1.44, 3.03) <.001 2.64 (1.80, 3.87) <.001 2.16 (1.54, 3.02) OR, odds ratio; HR, hazard ratio; CI, confidence interval; mutated, mut; wild-type, wt. ORs > (<) 1.0 mean higher (lower) CR rate, and HRs > (<) 1.0 mean higher (lower) risk for relapse or death (DFS, EFS), respectively, for the higher values of the continuous variables and the first category listed for the categorical variables. Variables significant at α =.20 in univariable models were considered, although all considered variables are not shown. *There are interactions between GAS6 and TYRO3/AXL dual receptor status for DFS (P=.16), OS (P=.06) and EFS (P=.12). The P-values, HRs and CIs are for comparisons of GAS6+ v GAS6– pts within the TYRO3–/AXL– subset. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A 17-Gene Leukemia Stem Cell (LSC) Score in Adult Patients (Pts) with Acute Myeloid Leukemia (AML) Reveals a Distinct Mutational Landscape and Refines Current European Leukemianet (ELN) Genetic Risk Stratification

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 289-289 ◽  
Author(s):  
Marius Bill ◽  
Deedra Nicolet ◽  
Ann-Kathrin Eisfeld ◽  
Krzysztof Mrózek ◽  
Christopher J. Walker ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Expression Data ◽  
Age Related ◽  
Mutational Status ◽  
Multivariable Analyses ◽  
De Novo Aml ◽  
Favorable Group

Abstract Introduction: Prognosis of AML pts is still poor mainly because of refractoriness to or relapse after intensive chemotherapy. High rates of relapse are also attributed to LSCs, which are a small subset of cells with acquired abnormal self-renewal capacity and increased resistance to chemotherapy. A better understanding of LSCs is critical to improve outcomes of pts with AML. Ng et al. (Nature 2016;540:433) defined a 17 stemness-associated gene score that was highly prognostic. Aims: The aim of this study was to validate the prognostic relevance of the 17-gene LSC score and explore its utility in the context of the ELN classification. We also examined gene mutations associated with the 17-gene LSC score. Methods: We analyzed a total of 934 pts [729 aged <60 years (y) and 205 aged ≥60 y] with de novo AML. We used whole transcriptome expression data (RNAseq) to calculate the aforementioned 17-gene LSC score for each pt in our cohort. Similar to Ng et al., we used the median of the whole cohort to discriminate between pts with LSChigh and LSClow scores. The mutational status of 80 cancer- and leukemia-associated genes (Eisfeld et al. Leukemia 2017;31:2211) were determined using a targeted next-generation sequencing panel, CEBPA mutations using Sanger sequencing, and an internal tandem duplication (ITD) of the FLT3 gene using fragment analysis in pretreatment bone marrow or blood samples. All pts were treated on frontline Cancer and Leukemia Group B/Alliance protocols. Results: A comparison of pretreatment clinical and genetic features revealed that LSChigh pts were older (P<.001; median age, 53 vs 46 y) and had higher platelet counts (P<.001; median, 63 vs 50x109/L) than LSClow pts. Pts with a LSChigh score more frequently had FLT3-ITD (P<.001) and mutations in the ASXL1 (P=.001), DNMT3A (P<.001), RUNX1 (P=.002), SRSF2 (P=.02), STAG2 (P=.009), TET2 (P=.008) and TP53 (P<.001) genes. Conversely, these pts had a lower frequency of biallelic CEBPA (P<.001), GATA2 (P=.008) and KIT (P<.001) mutations. Because of differences in treatment intensity, we analyzed outcomes of younger and older pts separately. Younger pts with a LSChigh score had a lower complete remission (CR) rate (P<.001; 63% vs 87%), shorter disease-free survival (DFS; P<.001; 3-y rates, 26% vs 48%; Figure 1A) and overall survival (OS; P<.001; 3-y rates, 27% vs 59%; Figure 1B) compared to those of LSClow pts. In multivariable analyses including clinical and genetic factors that impact on outcome, a LSChigh score associated with lower remission rates (P<.001; HR: 0.36), shorter DFS (P<.001; HR: 1.67) and OS (P<.001; HR: 1.88) after adjusting for other co-variates. We also analyzed the prognostic impact of the LSC score with respect to the 2017 ELN classification. We found that LSC score associated with different ELN groups (P<.001), with LSChigh pts being more often classified in the Adverse or Intermediate group and less often in the Favorable group. Within the ELN Favorable and Adverse groups, LSChigh score retained its prognostic impact and identified pts with a lower CR rate and shorter DFS and OS (Table1). In older pts, a LSChigh score also associated with lower CR rate (P=.004; 50% vs 72%), shorter DFS (P=.04; 3-y rates, 6% vs 17%; Figure 1C) and OS (P<.001; 3-y rates, 9% vs 27%; Figure 1D). In multivariable analyses, LSC score remained significant only for OS (P<.003; HR: 1.70) after adjusting for other co-variates. Regarding the ELN classification, pts with LSChigh score in the Favorable group had shorter OS (P=.05; 3-y rates, 17% vs 50%) and, by trend, shorter DFS (P=.09; 3-y rates, 17% vs 39%); no significant differences were found in Intermediate or Adverse groups. Conclusions: We used RNAseq expression data and applied the previously established 17-gene LSC signature to score 934 de novo AML pts. We detected distinct mutational differences between LSChigh and LSClow pts, with LSChigh pts more often carrying gene mutations associated with age-related clonal hematopoiesis (i.e., ASXL1, DNMT3A, TET2, SRSF2 and TP53 mutations). Moreover, this score, derived from the expression of stemness-associated genes, has not only a prognostic impact on its own but also in the context of the current 2017 ELN classification. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

AML with RUNX1 Mutations and Loss of RUNX1 Wild-Type - a Distinct Subset?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2578-2578
Author(s):  
Claudia Haferlach ◽  
Niroshan Nadarajah ◽  
Annette Fasan ◽  
Karolína Perglerová ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosome 21 ◽  
Prognostic Impact ◽  
Wild Type ◽  
Mutation Load ◽  
Employment Equity ◽  
Runx1 Gene ◽  
Equity Ownership ◽  
De Novo Aml ◽  
Runx1 Mutation

Abstract Background: Mutations in RUNX1 have been reported in 5 to 20% of AML. RUNX1 mutated AML is associated with a myeloid rather than monocytic differentiation, shows a typical pattern of cytogenetic abnormalities with a high frequency of trisomy 8 or 13, has a typical pattern of additional molecular mutations with a high frequency of accompanying ASXL1 and SF3B1 mutations and is nearly mutually exclusive of NPM1 and CEBPA double mutations and other entity-defining genetic abnormalities. In a subset of patients with RUNX1 mutations loss of the wild-type allele can be assumed due to a high mutation load. The aim of this study was the detailed analysis of a subset of RUNX1 mutated AML with RUNX1 wild-type loss with respect to accompanying cytogenetic and molecular genetic abnormalities and prognostic impact. Patients and Methods: A cohort of 467 AML with RUNX1 mutations (mut) at diagnosis identified during diagnostic work-up in our laboratory were the basis of this study. Median age was 72 years (yrs) (range 18-91 yrs), and male:female ratio 296: 171. 366 patients had de novo AML, 77 s-AML following MDS, 24 t-AML. For all patients (pts) cytogenetics and for 341 data on FAB subtype was available. Mutation data was available for NPM1 (n=456), MLL-PTD (n=453), CEBPA (n=449), FLT3-ITD (n=457), FLT3-TKD (n=457), WT1 (n=398), ASXL1 (n=313), TP53 (n=231), DNMT3A (n=177), TET2 (n=174), NRAS (n=305), KRAS (n=213) and SF3B1 (n=119). 64 patients with a mutation load of RUNX1 mutation >70% evaluated by sequencing analysis were selected for further analysis. All 64 cases were analysed by genomic arrays (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany) to determine the copy number state and copy neutral loss of heterozygosity (CN-LOH). Median age was 73 yrs (range 24-87 yrs), and male:female ratio was 27: 37. 50 patients had de novo AML, 11 s-AML following MDS, 3 t-AML. Results: Array CGH revealed a cytogenetically cryptic deletion on the long arm of chromosome 21 encompassing the RUNX1 gene in 5/64 (8%) patients while a CN-LOH on 21q including the RUNX1 gene was observed in 45 cases (70%). Thus in 50 cases (78%) with a high RUNX1 mutation load a RUNX1 wild-type loss (wt-loss) was detected by array CGH. In 43% (6/14) of the remaining cases the high RUNX1 mutation load was caused by amplification of the long arm of chromosome 21 either due to gain of whole chromosomes 21 or to an isochromosome 21q. First we focused on the characterization of RUNX1 mutated cases with RUNX1 wt-loss. In 22/50 cases (44%) an aberrant karyotype was observed with a distinct aberration pattern. 11 cases harbored +13, 5 had +8 and 6 cases a loss of 7q. No other recurrent abnormalities were observed. With respect to concurrent mutations the following frequencies were found: ASXL1 (42%), FLT3 -ITD (34%), TET2 (21%), KRAS (11%), MLL-PTD (8%), NRAS (7%), and FLT3-TKD (6%). No NPM1 mutation or CEBPA double mutations were identified. Comparison of those cases with RUNX1 wt-loss to all other RUNX1 mutated AML (n=417) revealed a significantly higher frequency of +13 (22% vs 9%, p=0.01) and FLT3 -ITD (34% vs 19%, p=0.015). FAB subtypes M0 and M1 were more frequent (46% vs 12%, p<0.001; 35% vs 22%, n.s.) and M2 and M4 less frequent (14% vs 46%, p<0.0001; 5% vs 17%, n.s.). Survival analyses were restricted to 212 de novo AML pts with RUNX1 mut who received intensive chemotherapy (median overall survival (OS): 20 months (mo), median event-free survival (EFS): 12 mo). Median OS and EFS was shorter in patients with RUNX1 wt-loss compared to those without (15 vs 20 mo, n.s., 10 vs 12 mo, p=0.04). In univariate Cox regression analysis a negative impact on OS was observed for RAS mut (relative risk (RR): 2.2, p=0.005), male gender (RR: 1.6, p=0.02), and age (RR: 1.3 per decade, p<0.001). Shorter EFS was associated with RUNX1 wt-loss (RR: 1.7, p=0.04), RAS mut (RR: 1.9, p=0.02) and age (RR: 1.2 per decade, p<0.001). In multivariate analysis RAS mut (OS: RR: 2.4, p=0.002; EFS: RR: 2.0, p=0.008) and age (OS: RR: 1.3 per decade, p<0.001; EFS: RR: 1.2 per decade, p<0.001) had independent prognostic impact. Conclusions: RUNX1 mutated AML with wild-type loss is a distinct AML subset that does not overlap with any of the genetically defined WHO categories and is characterized by an immature phenotype (81% FAB Subtype M0 and M1) and a higher frequency of +13 and FLT3-ITD as compared to RUNX1 mutated AML without wild-type loss. Wild-type loss and RAS mutations are associated with inferior outcome in RUNX1 mutated AML. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Perglerová:MLL2 s.r.o.: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals Favorable Prognostic Impact ofNPM1Mutations in Older Patients With Cytogenetically Normal De Novo Acute Myeloid Leukemia and Associated Gene- and MicroRNA-Expression Signatures: A Cancer and Leukemia Group B Study

2010 ◽  
Vol 28 (4) ◽  
pp. 596-604 ◽  
Author(s):  
Heiko Becker ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Profiles ◽  
Age Groups ◽  
Microrna Expression ◽  
Prognostic Impact ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

PurposeTo analyze the prognostic significance of NPM1 mutations, and the associated gene- and microRNA-expression signatures in older patients with de novo, cytogenetically normal acute myeloid leukemia (CN-AML) treated with intensive chemotherapy.Patients and MethodsOne hundred forty-eight adults age ≥ 60 years with de novo CN-AML, enrolled onto Cancer and Leukemia Group B protocols 9720 and 10201, were studied at diagnosis for NPM1, FLT3, CEBPA, and WT1 mutations, and gene- and microRNA-expression profiles.ResultsPatients with NPM1 mutations (56%) had higher complete remission (CR) rates (84% v 48%; P < .001) and longer disease-free survival (DFS; P = .047; 3-year rates, 23% v 10%) and overall survival (OS; P < .001; 3-year rates, 35% v 8%) than NPM1 wild-type patients. In multivariable analyses, NPM1 mutations remained independent predictors for higher CR rates (P < .001) and longer DFS (P = .004) and OS (P < .001), after adjustment for other prognostic clinical and molecular variables. Unexpectedly, the prognostic impact of NPM1 mutations was mainly observed in patients ≥ 70 years. Gene- and microRNA-expression profiles associated with NPM1 mutations were similar across older patient age groups and similar to those in younger (< 60 years) patients with CN-AML. These profiles were characterized by upregulation of HOX genes and their embedded microRNAs and downregulation of the prognostically adverse MN1, BAALC, and ERG genes.ConclusionNPM1 mutations have favorable prognostic impact in older patients with CN-AML, especially those age ≥ 70 years. The gene- and microRNA-expression profiles suggest that NPM1 mutations constitute a marker defining a biologically homogeneous entity in CN-AML that might be treated with specific and/or targeted therapies across age groups.

scholarly journals Aging shapes the population-mean and ‐dispersion of gene expression in human brains

2016 ◽  
Author(s):  
Candice L. Brinkmeyer-Langford ◽  
Jinting Guan ◽  
Guoli Ji ◽  
James J. Cai
Keyword(s):  
Gene Expression ◽  
Age Groups ◽  
Tissue Expression ◽  
Brain Regions ◽  
Tissue Samples ◽  
Protein Coding ◽  
Age Related ◽  
Increased Risk ◽  
Neurotransmitter Transport ◽  
Human Brains

AbstractHuman aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx) data from 54 and 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1,446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals’ genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases.

scholarly journals Age-Related Changes of Gene Expression Profiles in Drosophila

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1982
Author(s):  
Guillaume Bordet ◽  
Niraj Lodhi ◽  
Andrew Kossenkov ◽  
Alexei Tulin
Keyword(s):  
Gene Expression ◽  
Muscle Development ◽  
Expression Profiles ◽  
Age Groups ◽  
Gene Expression Profiles ◽  
Age Related ◽  
Profile Changes ◽  
Flight Muscles ◽  
And Function ◽  
Different Levels

An individual’s gene expression profile changes throughout their life. This change in gene expression is shaped by differences in physiological needs and functions between the younger and older organism. Despite intensive studies, the aging process is not fully understood, and several genes involved in this process may remain to be identified. Here we report a transcriptomic analysis of Drosophila melanogaster using microarrays. We compared the expression profiles of two-day-old female adult flies with those of 45-day-old flies. We identified 1184 genes with pronounced differences in expression level between young and old age groups. Most genes involved in muscle development/maintenance that display different levels of expression with age were downregulated in older flies. Many of these genes contributed to sarcomere formation and function. Several of these genes were functionally related to direct and indirect flight muscles; some of them were exclusively expressed in these muscles. Conversely, several genes involved in apoptosis processes were upregulated in aging flies. In addition, several genes involved in resistance to toxic chemicals were upregulated in aging flies, which is consistent with a global upregulation of the defense response system in aging flies. Finally, we randomly selected 12 genes among 232 genes with unknown function and generated transgenic flies expressing recombinant proteins fused with GFP protein to determine their subcellular expression. We also found that the knockdown of some of those 12 genes can affect the lifespan of flies.

Aberrant Gene Expression of BAALC and ERG in Older [≥60 Years (y)] De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 214-214
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Internal Control ◽  
Hox Genes ◽  
Conflicts Of Interest ◽  
Age Groups ◽  
Prognostic Impact ◽  
Stem Cell Markers ◽  
Down Regulation ◽  
Expression Levels ◽  
Lower Expression

Abstract Abstract 214 BAALC & ERG are aberrantly expressed in younger (<60 y) adult CN-AML patients (pts), where expression levels of these genes are also associated with clinical outcome. Whether aberrant BAALC & ERG expression also occurs in older (≥60 y) CN-AML pts is unknown. To assess the BAALC & ERG expression levels in older CN-AML & their impact on outcome we studied pts ≥60 y (median age, 68 y; range 60–83) enrolled on cytarabine/daunorubicin-based protocols [CALGB 10201, 9720, 9420, 8923, 8525], with diagnostic blood samples available for quantitative RT-PCR analysis (n=158), that were also characterized for other molecular prognosticators (FLT3-ITD, FLT3-TKD, NPM1 & WT1 mutations). BAALC & ERG expression values were normalized to an internal control (ABL1), & the median gene expression value was used to define high & low expressers for BAALC & ERG. Gene (GEP) & microRNA (MEP) expression profiling were done using, respectively, Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays. At diagnosis, lower BAALC expression was associated with mutated NPM1 (P<.001) & low ERG expression (P<.001). Lower BAALC expressers had a higher complete remission rate (CR; 86% v 54%, P<.001) & longer disease-free (DFS; P=.006; 3y rates 19% v 12%) & overall survival (OS; P<.001; 3y 29% v 10%) than higher expressers. Lower ERG expression was associated with lower WBC (P=.005), % marrow (BM; P=.001) & blood (P<.001) blasts & absent FLT3-ITD (P<.001) & low BAALC expression (P<.001). Lower ERG expression also associated with longer DFS (P=.001; 3y 18% v 14%) & OS (P<.001; 3y 24% v 15%). In multivariable models (Table 1), low BAALC expression independently associated with CR & longer DFS. BAALC & ERG expression were the only factors associated with OS. Comparison of age-groups (60-69 y v ≥70 y; Table 2) showed BAALC expression had a stronger prognostic impact in ≥70 y pts; lower expression was associated with higher CR rates & longer DFS & OS. ERG expression had instead stronger prognostic impact in 60-69 y pts (Table 2); lower expression was associated with longer DFS & OS. GEP (482 probes) & MEP (22 probes) differentiated low from high BAALC expressers. Low BAALC expressers had down-regulation of stem cell markers (CD34, CD133) & unfavorable outcome predictors (HGF, MN1, CD200), & up-regulation of HOX genes & miR-10a & miR-10b. GEP (1554 probes) & MEP (11 probes) differentiating low from high ERG expressers showed low ERG expressers had down-regulation of DNMT3B & up-regulation of topoisomerase 1 (TOP1), which is associated with enhanced chemotherapy sensitivity. Among up-regulated microRNAs in low ERG expressers was miR-208a, which is predicted to target ERG. In conclusion, lower expression of both BAALC & ERG associated with better outcome in older CN-AML pts even in the context of other established prognostic molecular markers, but have different impact on age-groups. GEP & MEP provided novel information that may elucidate how differential expression levels of these genes contribute to leukemogenesis & aid in developing novel risk-adapted therapies. Disclosures: No relevant conflicts of interest to declare.

Frequency and Prognosis of JAK2 V617F, Calr, MPL and ASXL1 Mutations in Primary Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5562-5562
Author(s):  
Marc Sorigue ◽  
Marta Cabezón ◽  
Olga Garcia ◽  
Patricia Velez ◽  
Silvia Marce ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak2 V617f Mutation ◽  
Prognostic Impact ◽  
Wild Type ◽  
Exon 9 ◽  
V617f Mutation ◽  
Calr Mutations ◽  
Exon 10

Abstract INTRODUCTION: Several mutations have been described in patients with BCR-ABL1 –negative chronic myeloproliferative neoplasms, including primary myelofibrosis (PMF). The most frequent mutation is JAK2 V617F, followed by calreticulin exon 9 (CALR), MPL exon 10 and ASXL1 exon 12. Currently, less than 10% of patients lack molecular marker. CALR and ASXL1 mutations have been consistently found to have favorable and unfavorable prognostic implications, respectively. The aim of this study was to describe the frequency and prognostic impact of JAK2 V617F, CALR, MPL and ASXL1 mutations in patients diagnosed with PMF in 6 Spanish hospitals. METHODS: To detect the presence of JAK2 V617F mutation, an allele-specific PCR using TaqMan probes was used. Screening for insertions and deletions in CALR gene was performed with 6-FAM labeled primers spanning exon 9 and CALR mutations were described by Sanger sequencing. Sanger sequencing was also used to detect MPL exon 10 and ASXL1 exon 12 mutations. RESULTS: Sixty-eight patients were included in the study. All of them were screened for JAK2 and CALR mutations. Forty-five of them (66%) were positive for the JAK2 V617F mutation, while 11/68 (16%) were positive for CALR mutations. Of the 11 CALR mutations, 10 were JAK2 wild-type. MPL exon 10 mutation analysis was only performed in JAK2 wild-type patients and was positive in 4/23 patients (17%), and all of them were CALR wild-type. At the time of submission, ASXL1 exon 12 has been assessed in 18 patients (analysis in the rest of them is currently ongoing). ASXL1 mutations have been found in 3/18 (17%) patients, two of them also with a CALR mutation and the other one with the JAK2 V617F mutation. All three cases were indel mutations. Overall, no mutation was detected in 9/68 (13%) patients. JAK2 V617F, CALR and MPL mutations had no prognostic impact on overall survival. The effect of ASXL1 mutation on prognosis (with and without CALR mutation) will be assessed once all samples have been sequenced. CONCLUSION: JAK2 V617F, CALR and MPL mutations were found in our series of PMF patients in the same proportion found in larger series. ASXL1 has so far been found in a smaller percentage but the entire series of patients will need to be sequenced before reaching definitive conclusions. Studying these genes, only 13% of patients with PMF did not have a clonal marker. None of the studied mutations had prognostic significance. ACKNOWLEDGMENTS: The authors would like to thank Diana Dominguez for her excellent technical assistance and to the grant 2014 SGR225 (GRE), Generalitat de Catalunya. Disclosures No relevant conflicts of interest to declare.

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