Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics

Abstract The prognostic impact of trisomy 8, alone or with other clonal aberrations, was evaluated in 849 patients with previously untreated acute myeloid leukemia (AML) who were registered to 5 Southwest Oncology Group trials. At presentation, 108 (12.7%) patients had +8 in their karyotypes, including 43 (5.1%) patients with +8 as the sole aberration; 307 (36.2%) were normal, and 434 (51.1%) had other cytogenetic abnormalities. Patients with +8 were slightly older (P = .033), had lower WBC (P = .011), and had lower percentages of peripheral blasts (P = .0004) than the patients without +8. Median survival time for all patients with +8 was 9.9 months (95% CI, 6.5-12.5), similar to that of “unfavorable” cytogenetics risk groups (8.3 months; 95% CI, 6.8-9.5.) Patients with +8 had significantly lower peripheral blasts (P = .0002), WBC (P < .0001) counts, and decreased overall survival (OS) than patients with normal cytogenetics (9.9 months vs 15.4 months; P = .006). However, survival of patients with +8 as the sole aberration did not differ significantly from those with normal cytogenetics (P = .36). Thus, the trisomy 8 group as a whole had poor survival, which was largely attributable to worsened outcomes among patients whose trisomy 8 was associated with other unfavorable cytogenetic abnormalities.

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MicroRNA expression profiling in Acute myeloid leukemia patients

Klinische Pädiatrie ◽

10.1055/s-0029-1222631 ◽

2009 ◽

Vol 221 (03) ◽

Author(s):

S Daschkey ◽

T Haferlach ◽

A Borkhardt ◽

P Landgraf

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Myeloid Leukemia ◽

Microrna Expression ◽

Acute Myeloid

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Functional implications of microRNAs in acute myeloid leukemia by integrating microRNA and messenger RNA expression profiling

Cancer ◽

10.1002/cncr.26096 ◽

2011 ◽

Vol 117 (20) ◽

pp. 4696-4706 ◽

Cited By ~ 42

Author(s):

Violaine Havelange ◽

Nicole Stauffer ◽

Catherine C. E. Heaphy ◽

Stefano Volinia ◽

Michael Andreeff ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Expression Profiling ◽

Messenger Rna ◽

Myeloid Leukemia ◽

Rna Expression ◽

Functional Implications ◽

Rna Expression Profiling ◽

Acute Myeloid

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Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup

Haematologica ◽

10.3324/haematol.11100 ◽

2007 ◽

Vol 92 (6) ◽

pp. 763-770 ◽

Cited By ~ 30

Author(s):

M. Schaich ◽

R. F. Schlenk ◽

H. K. Al-Ali ◽

H. Dohner ◽

A. Ganser ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Individual Patient Data ◽

Meta Analysis ◽

Patient Data ◽

Complex Karyotype ◽

Trisomy 8 ◽

Acute Myeloid

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Tritsomy 8 Acute Myeloid Leukemia Analysis Reveals New Insights of DNA Methylome with Identification of HHEX as Potential Diagnostic Marker

Biomarkers in Cancer ◽

10.4137/bic.s19614 ◽

2015 ◽

Vol 7 ◽

pp. BIC.S19614 ◽

Cited By ~ 4

Author(s):

Marwa H. Saied ◽

Jacek Marzec ◽

Sabah Khalid ◽

Paul Smith ◽

Gael Molloy ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Diagnostic Marker ◽

Cpg Island ◽

Global Analysis ◽

Extra Chromosome ◽

Chromosome 8 ◽

Trisomy 8 ◽

Acute Myeloid

Trisomy 8 acute myeloid leukemia (AML) is the commonest numerical aberration in AML. Here we present a global analysis of trisomy 8 AML using methylated DNA immunoprecipitation-sequencing (MeDIP-seq). The study is based on three diagnostic trisomy 8 AML and their parallel relapse status in addition to nine non-trisomic AML and four normal bone marrows (NBMs). In contrast to non-trisomic DNA samples, trisomy 8 AML showed a characteristic DNA methylation distribution pattern because an increase in the frequency of the hypermethylation signals in chromosome 8 was associated with an increase in the hypomethylation signals in the rest of the chromosomes. Chromosome 8 hypermethylation signals were found mainly in the CpG island (CGI) shores and interspersed repeats. Validating the most significant differentially methylated CGI ( P = 7.88 · 10–11identified in trisomy 8 AML demonstrated a specific core region within the gene body of HHEX, which was significantly correlated with HHEX expression in both diagnostic and relapse trisomy 8 AMLs. Overall, the existence of extra chromosome 8 was associated with a global impact on the DNA methylation distribution with identification of HHEX gene methylation as a potential diagnostic marker for trisomy 8 AML.

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Mutational profiling of acute myeloid leukemia with normal cytogenetics in Brazilian patients: the value of next-generation sequencing for genomic classification

Journal of Investigative Medicine ◽

10.1136/jim-2017-000566 ◽

2017 ◽

Vol 65 (8) ◽

pp. 1155-1158 ◽

Cited By ~ 6

Author(s):

Thiago Rodrigo de Noronha ◽

Miguel Mitne-Neto ◽

Maria de Lourdes Chauffaille

Keyword(s):

Acute Myeloid Leukemia ◽

Next Generation Sequencing ◽

Myeloid Leukemia ◽

Regulation Of Gene Expression ◽

Uniparental Disomy ◽

Driver Mutations ◽

Next Generation ◽

Normal Cytogenetics ◽

Generation Sequencing ◽

Acute Myeloid

Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients’ risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation:DNMT3Ain nine patients;IDH2in six;IDH1in three;NRASandNPM1in two; andTET2,ASXL1,PTPN11, andRUNX1in one patient. No mutations were found inFLT3,KIT,JAK2,CEBPA,GATA2,TP53,BRAF,CBL,KRAS,andWT1genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation (DNMT3A,IDH1,IDH2,andTET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.

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The possible significance of trisomy 8 in acute myeloid leukemia

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20172464 ◽

2017 ◽

Vol 5 (6) ◽

pp. 2652 ◽

Cited By ~ 2

Author(s):

Salil N. Vaniawala ◽

Monika V. Patel ◽

Pratik D. Chavda ◽

Shivangi H. Zaveri ◽

Pankaj K. Gadhia

Keyword(s):

Acute Myeloid Leukemia ◽

Chromosomal Aberrations ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Prognostic Significance ◽

Chromosomal Translocation ◽

Banding Technique ◽

Trisomy 8 ◽

Increased Risk ◽

Acute Myeloid

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder that results from a block in the differentiation of haematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 is the most common recurring numerical chromosomal aberrations in acute myeloid leukemia (AML). It occurs either as a sole anomaly or together with other additional chromosomal aberrations. The prognostic significance of trisomy 8 in presence of other additional chromosomal abnormality depends on clonal cytogenetic changes. The patients with trisomy 8 had shorter survival with significantly increased risk with other chromosomal abnormality.Methods: Total 139 patients were screened between January 2016 to November 2016 who were suspected of AML cases. Bone marrow cultures were set up using conventional cytogenetic methods. Chromosomal preparation was made and subjected to GTG banding technique. Banded metaphases were analysed and karyotyped for further analysis.Results: Cytogenetic evaluation of karyotyped of 139 suspected AML patients showed 52 with t(8;21)(q22;q22), 36 with t(15;17)(q22;q12), and 11 with inv(16)(p13;q22). The rest 40 cases found with additional chromosomal abnormalities, of which 16 were sole trisomy 8 and 24 cases were found with other chromosomal abnormalities In addition, only one person found with t(8;21) and trisomy 8, while three person having t(15;17) with trisomy 8.Conclusions: AML is considered to be one of the most important cytogenetic prognostic determinants. Recurrent chromosomal translocation with trisomy 8 varying 1.9% for t(8;21) and 8.3% for t(15;17). In the present study trisomy 8 in AML with known favourable anomalies is very small. Therefore, it cannot be taken as a prognostic marker.

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MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia

Blood ◽

10.1182/blood-2007-07-098749 ◽

2008 ◽

Vol 111 (6) ◽

pp. 3183-3189 ◽

Cited By ~ 446

Author(s):

Ramiro Garzon ◽

Stefano Volinia ◽

Chang-Gong Liu ◽

Cecilia Fernandez-Cymering ◽

Tiziana Palumbo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Mirna Expression ◽

Myeloid Leukemia ◽

Cox Regression ◽

Independent Set ◽

Microarray Platform ◽

Small Subset ◽

Trisomy 8 ◽

Molecular Abnormalities ◽

Acute Myeloid

Abstract MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are negative regulators of gene expression. To determine whether miRNAs are associated with cytogenetic abnormalities and clinical features in acute myeloid leukemia (AML), we evaluated the miRNA expression of CD34+ cells and 122 untreated adult AML cases using a microarray platform. After background subtraction and normalization using a set of housekeeping genes, data were analyzed using Significance Analysis of Microarrays. An independent set of 60 untreated AML patients was used to validate the outcome signatures using real-time polymerase chain reaction. We identified several miRNAs differentially expressed between CD34+ normal cells and the AML samples. miRNA expression was also closely associated with selected cytogenetic and molecular abnormalities, such as t(11q23), isolated trisomy 8, and FLT3-ITD mutations. Furthermore, patients with high expression of miR-191 and miR-199a had significantly worse overall and event-free survival than AML patients with low expression (overall survival: miR-191, P = .03; and miR-199a, P = .001, Cox regression). In conclusion, miRNA expression in AML is closely associated with cytogenetics and FLT3-ITD mutations. A small subset of miRNAs is correlated with survival.

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