Leukemia diagnosis: today and tomorrow

Béné, Marie C.; Grimwade, David; Haferlach, Claudia; Haferlach, Torsten; Zini, Gina

doi:10.1111/ejh.12603

Cited by 23 publications

(12 citation statements)

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“…We show that gene panel testing by NGS approach in a diagnostic molecular pathology laboratory allows sensitive and accurate detection of actionable AML gene mutations to individualize patient management. The diagnostic approach to AML is facing a paradigm shift in the genomics era [ 44 ]. As more targeted therapy become available, the greater is the clinical demand for comprehensive molecular profiling.…”

Section: Discussionmentioning

confidence: 99%

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Au¹,

Wa²,

Ho³

et al. 2016

Diagn Pathol

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BackgroundGenomic techniques in recent years have allowed the identification of many mutated genes important in the pathogenesis of acute myeloid leukemia (AML). Together with cytogenetic aberrations, these gene mutations are powerful prognostic markers in AML and can be used to guide patient management, for example selection of optimal post-remission therapy. The mutated genes also hold promise as therapeutic targets themselves. We evaluated the applicability of a gene panel for the detection of AML mutations in a diagnostic molecular pathology laboratory.MethodsFifty patient samples comprising 46 AML and 4 other myeloid neoplasms were accrued for the study. They consisted of 19 males and 31 females at a median age of 60 years (range: 18–88 years). A total of 54 genes (full coding exons of 15 genes and exonic hotspots of 39 genes) were targeted by 568 amplicons that ranged from 225 to 275 bp. The combined coverage was 141 kb in sequence length. Amplicon libraries were prepared by TruSight myeloid sequencing panel (Illumina, CA) and paired-end sequencing runs were performed on a MiSeq (Illumina) genome sequencer. Sequences obtained were analyzed by in-house bioinformatics pipeline, namely BWA-MEM, Samtools, GATK, Pindel, Ensembl Variant Effect Predictor and a novel algorithm ITDseek.ResultsThe mean count of sequencing reads obtained per sample was 3.81 million and the mean sequencing depth was over 3000X. Seventy-seven mutations in 24 genes were detected in 37 of 50 samples (74 %). On average, 2 mutations (range 1–5) were detected per positive sample. TP53 gene mutations were found in 3 out of 4 patients with complex and unfavorable cytogenetics. Comparing NGS results with that of conventional molecular testing showed a concordance rate of 95.5 %. After further resolution and application of a novel bioinformatics algorithm ITDseek to aid the detection of FLT3 internal tandem duplication (ITD), the concordance rate was revised to 98.2 %.ConclusionsGene panel testing by NGS approach was applicable for sensitive and accurate detection of actionable AML gene mutations in the clinical laboratory to individualize patient management. A novel algorithm ITDseek was presented that improved the detection of FLT3-ITD of varying length, position and at low allelic burden.

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Section: Discussionmentioning

confidence: 99%

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Au¹,

Wa²,

Ho³

et al. 2016

Diagn Pathol

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“…Acute myeloid leukemia (AML) comprises a biologically and genetically heterogeneous group of disorders characterized by the rapid expansion of immature myeloid blasts in bone marrow (BM) (Bene et al., 2015, Grimwade et al., 2016). Disease heterogeneity is well documented and patients are stratified based on cytogenetic, molecular, and immunophenotypic data.…”

Section: Introductionmentioning

confidence: 99%

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

et al. 2017

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SummaryBone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.

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“…With the increasing number of participants from the Americas and Asia, the ELN has evolved from a European to an international network. Some of the more recent ELN recommendations are listed in Table …”

Section: Recommendations and Guidelines: 2013 To 2017mentioning

confidence: 99%

Advancing a field by building consortia: The example of the European LeukemiaNet

Hehlmann

2018

Cancer

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Leukemia diagnosis: today and tomorrow

Cited by 23 publications

References 50 publications

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

Advancing a field by building consortia: The example of the European LeukemiaNet

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