Next-Generation Sequencing in Acute Lymphoblastic Leukemia

Coccaro, Nicoletta; Anelli, Luisa; Zagaria, Antonella; Specchia, Giorgina; Albano, Francesco

doi:10.3390/ijms20122929

Cited by 73 publications

(75 citation statements)

References 146 publications

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“…In children, ALL is the most common cancer associated with high cure rates of about 85%. In adults, ALL accounts for 15-25% of acute leukaemias and is associated with a less favourable outcome [Mohseni et al, 2018, Coccaro et al, 2019Follini et al, 2019;Pavlovic et al, 2019]. Among ALLs, T-ALL is responsible for approximately 15% of paediatric ALLs and 25% of adult ALLs [Follini et al, 2019].…”

Section: Introductionmentioning

confidence: 99%

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

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The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineagespecific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.

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Section: Introductionmentioning

confidence: 99%

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

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“…5,6 For patients with relapsed/refractory disease, outcomes are dismal, with cure achieved in <10% in several studies when combination salvage chemotherapy is used. 7,8 Recent years have witnessed the development of more sophisticated means of characterizing tumor biology, 9 extremely sensitive assays used to assess residual disease burden, 10,11 and accelerated development of several novel targeted therapies. 12 These advancements have resulted in significant improvements in the treatment of adult ALL subtypes, particularly in the relapsed/refractory setting.…”

Section: Introductionmentioning

confidence: 99%

<p>Blinatumomab for the Treatment of Adult B-Cell Acute Lymphoblastic Leukemia: Toward a New Era of Targeted Immunotherapy</p>

Franquiz¹,

Short²

2020

BTT

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Several therapeutic advancements in the treatment of B-cell acute lymphoblastic leukemia (ALL) have surfaced in the past decade, primarily driven by an increased understanding of the immunopathobiology of this disease. The clinical use of blinatumomab, a bispecific antibody that coordinates cytotoxic CD3+ T lymphocytes and CD19+ lymphoblasts, has resulted in improved outcomes in both relapsed/refractory and minimal residual disease-positive B-cell ALL. Promising emerging data also demonstrate the efficacy of this agent in the frontline setting and in combination regimens. Uncertainty remains regarding the optimal sequencing and combination of blinatumomab with cytotoxic chemotherapy and other emerging agents. The pharmacology and clinical data on blinatumomab for adult B-cell ALL, both as monotherapy and in combinations, will be reviewed herein.

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“…NGS has led to the identification of many newer molecular entities of ALL and has also provided a more profound understanding of the ones that are already known [ 7 ]. Both B cell ALL and T cell ALL are comprised of multiple subtypes defined by structural DNA alterations as an initiating lesion, with secondary somatic (tumor acquired) alterations and sequence mutation, which jointly contribute to leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…In clinical practice, genetic analysis is conducted through the low throughput techniques like low-density arrays (LDA), fluorescence in situ hybridization (FISH), and Q-PCR. These techniques identify a limited number of detectable alterations but are still primarily used worldwide [ 7 ]. NGS has improved our understanding of disease pathogenesis and has also helped identify key biomarkers that are of diagnostic and prognostic importance.…”

Section: Introductionmentioning

confidence: 99%

Integration of Next-Generation Sequencing in Diagnosing and Minimal Residual Disease Detection in Patients With Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

Sherali

Hamadneh

Aftab

et al. 2020

Cureus

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Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype of B cell ALL. It accounts for 20% of all B cell ALL cases and is similar to BCR-ABL1 in gene expression profile but lacks BCR-ABL fusion. It is highly heterogeneous and is characterized by genetic alterations that activate kinase and cytokine receptor signaling. Most of these alterations are amenable to tyrosine kinase inhibitors. Ph-like ALL is prevalent in pediatric and young adults, more common in males, and frequently seen in patients with Hispanic ancestry. It is associated with inadequate response to induction therapy, high minimal residual disease (MRD) levels, and increased risk of relapse. Overall survival and event-free survival are also inferior in these patients as compared to non-Ph-like ALL. In the clinical practice, low-density array, real-time quantitative polymerase chain reaction (RQ-PCR), flow cytometry, fluorescence in situ hybridization are used to identify genetic alteration in these patients. With the advent of next-generation sequencing (NGS), our understanding of disease pathogenesis and precision medicine has been improved. In this review, we analyzed data from several studies that used NGS as one of the diagnostic methods to identify genomic lesions in this high-risk subtype of B cell ALL. Studies have shown that NGS is a vital technique to identify various genomic lesions at diagnosis and throughout the treatment that can be missed by the widely used current methods. NGS has improved our understanding of various genomic lesions associated with Ph-like ALL and has helped define disease pathogenesis, MRD evaluation, and stratify therapy to prevent over or under treatment. We are in the era of precision medicine. Therefore unbiased, comprehensive genomic characterization of Ph-like ALL is important to implicate treatment directed against these genomic lesions and improve outcomes in these patients. We also analyzed data from studies that compared NGS with multi-flow cytometry and RQ-PCR for the evaluation of MRD. In the future, more extensive prospective studies are required to confirm the prognostic usefulness of NGS.

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Next-Generation Sequencing in Acute Lymphoblastic Leukemia

Cited by 73 publications

References 146 publications

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

<p>Blinatumomab for the Treatment of Adult B-Cell Acute Lymphoblastic Leukemia: Toward a New Era of Targeted Immunotherapy</p>

Integration of Next-Generation Sequencing in Diagnosing and Minimal Residual Disease Detection in Patients With Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia

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