Clinical benefit of a high‐throughput sequencing approach for minimal residual disease in acute lymphoblastic leukemia

Wright, Gary; Watt, Eleanor; Inglott, Sarah; Brooks, Tony; Bartram, Jack; Adams, Stuart

doi:10.1002/pbc.27787

Cited by 7 publications

(2 citation statements)

References 15 publications

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“…The advantages of MRD analysis using NGS are that very sensitive detection levels can be obtained using universal primer sets, allowing for the identification of unique targets within one procedure [86]. The disadvantages of NGS include large bioinformatic analysis challenges with low amounts of current laboratory standardization and quality assurance.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

Kruse

Abdel-Azim

Kim

et al. 2020

IJMS

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Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new diagnostic platforms, including next-generation sequencing (NGS), has introduced significant advances in the sensitivity of MRD diagnostics. Here, we review current methods to diagnose MRD through phenotypic marker patterns or differential gene patterns through analysis by flow cytometry (FCM), polymerase chain reaction (PCR), real-time quantitative polymerase chain reaction (RQ-PCR), reverse transcription polymerase chain reaction (RT-PCR) or NGS. Future advances in clinical procedures will be molded by practical feasibility and patient needs regarding greater diagnostic sensitivity.

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Section: Next-generation Sequencingmentioning

confidence: 99%

Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

Kruse

Abdel-Azim

Kim

et al. 2020

IJMS

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“…Several groups have shown the value of NGS technologies for MRD detection in precursor and mature B-cell tumors [13][14][15][16][17][18][56][57][58]. NGS can be used to detect clone-specific IG/TCR index sequences; clonal sequences detected at diagnosis can be re-detected and quantified in each follow-up sample.…”

Section: Next Generation Sequencingmentioning

confidence: 99%

Minimal residual disease in acute lymphoblastic leukemia: technical aspects and implications for clinical interpretation

Kim

2020

Blood Res

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Minimal residual disease (MRD) monitoring has proven to be one of the fundamental independent prognostic factors for patients with acute lymphoblastic leukemia (ALL). Sequential monitoring of MRD using sensitive and specific methods, such as real-time quantitative polymerase chain reaction (qPCR) or flow cytometry (FCM), has improved the assessment of treatment response and is currently used for therapeutic stratification and early detection. Although both FCM and qPCR yield highly consistent results with sensitivities of 10-4 , each method has several limitations. For example, qPCR is time-consuming and laborious: designing primers that correspond to the immunoglobulin (IG) and T-cell receptor (TCR) gene rearrangements at diagnosis can take 3-4 weeks. In addition, the evolution of additional clones beyond the first or index clone during therapy cannot be detected, which might lead to false-negative results. FCM requires experienced technicians and sometimes does not achieve a sensitivity of 10-4. Accordingly, a next generation sequencing (NGS)-based method has been developed in an attempt to overcome these limitations. With the advent of high-throughput NGS technologies, a more in-depth analysis of IG and/or TCR gene rearrangements is now within reach, which impacts all applications of IG/TR analysis. However, standardization, quality control, and validation of this new technology are warranted prior to its incorporation into routine practice.

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A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

Assing,

Jørgensen,

Sandgaard

et al. 2023

J Clin Immunol

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Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

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Clinical benefit of a high‐throughput sequencing approach for minimal residual disease in acute lymphoblastic leukemia

Cited by 7 publications

References 15 publications

Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia

Minimal residual disease in acute lymphoblastic leukemia: technical aspects and implications for clinical interpretation

A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

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