NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

Rosati, Emanuela; Baldoni, Stefano; Falco, Filomena De; Papa, Beatrice Del; Dorillo, Erica; Rompietti, Chiara; Albi, Elisabetta; Falzetti, Franca; Ianni, Mauro Di; Sportoletti, Paolo

doi:10.3389/fonc.2018.00229

Cited by 62 publications

(63 citation statements)

References 181 publications

(282 reference statements)

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“…To get a first expression, we filtered for aberrations smaller than 10kb, and for example identified two different SVs affecting NOTCH1 , being a 6kb deletion and a 3.3 kb insertion in sample 14 (CML) and 30 (MDS) respectively. This is a potentially interesting finding, as NOTCH 1 is an important leukemia driver gene in CLL, 34 but also emerges for other leukemia types. 35 Whether these two SVs add anything meaningful to our two cases requires further investigations though.…”

Section: Discussionmentioning

confidence: 73%

Next generation cytogenetics: comprehensive assessment of 48 leukemia genomes by genome imaging

Neveling

Mantere

Vermeulen

et al. 2020

Preprint

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Somatic structural variants are important for cancer development and progression. In a diagnostic set-up, especially for hematological malignancies, the comprehensive analysis of all cytogenetic aberrations in a given sample still requires a combination of techniques, such as karyotyping, fluorescence in situ hybridization and CNV-microarrays. We hypothesize that the combination of these classical approaches could be replaced by high-resolution genome imaging.Bone marrow aspirates or blood samples derived from 48 patients with leukemia, who received a clinical diagnoses of different types of hematological malignancies, were processed for genome imaging with the Bionano Genomics Saphyr system. In all cases cytogenetic abnormalities had previously been identified using standard of care workflows. Based on these diagnostic results, the samples were divided into two categories: simple cases (<5 aberrations, n=37) and complex cases (≥5 aberrations or an unspecified marker chromosome, n=11). By imaging the labelled ultra-long gDNA molecules (average N50 >250kb), we generated on average ∼280-fold mapped genome coverage per sample. Chromosomal aberrations were called by Bionano Genomics Rare variant pipeline (RVP) specialized for the detections of somatic variants.Per sample, on average a total of 1,454 high confidence SVs were called, and on average 44 (range: 14-130) of those were rare i.e. not present in the population control database. Importantly, for the simple cases, all clinically reported aberrations with variant allele frequencies higher than 10% were detected by genome imaging. This held true for deletions, insertions, inversions, aneuploidies and translocations. The results for the complex cases were also largely concordant between the standard of care workflow and optical mapping, and in several cases, optical mapping revealed higher complexity than previously known. SV and CNV calls detected by optical mapping were more complete than any other previous single test and likely delivered the most accurate and complete underlying genomic architecture. Even complex chromothripsis structures were resolved. Finally, optical mapping also identified multiple novel events, including balanced translocations that lead to potential novel fusion-genes, opening the potential to discover new prognostic and diagnostic biomarkers.The full concordance with diagnostic standard assays for simple cases and the overall great concordance with (previously likely incompletely understood) complex cases demonstrates the potential to replace classical cytogenetic tests with genome imaging. In addition, this holds the potential to rapidly map new fusion genes and identify novel SVs and CNVs as novel potential leukemia drivers.

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Section: Discussionmentioning

confidence: 73%

Next generation cytogenetics: comprehensive assessment of 48 leukemia genomes by genome imaging

Neveling

Mantere

Vermeulen

et al. 2020

Preprint

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“…There is growing evidence that links CLL to activated NOTCH signaling (7,8). CLL cells have a constitutive NOTCH1 and NOTCH2 activation contributing to apoptosis resistance (9).…”

Section: Introductionmentioning

confidence: 99%

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

Papa

Baldoni

Dorillo

et al. 2019

Clinical Cancer Research

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Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many offtarget effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response. Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the crosstalk between BTK and NOTCH1. Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphory-lation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells. Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments.

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confidence: 99%

“…leukemia in adult patients in Western countries [1][2][3]. NOTCH1 mutations associate with clinically aggressive forms of CLL and have emerged as an independent predictor of adverse prognosis [3]. Approximately 80% of NOTCH1 mutations in CLL consist of a 2-bp CT frameshift deletion (c.7541_7542delCT) that generates a truncation in the C-terminal PEST domain and prolongs the half-life of the active form of NOTCH1, i.e., the intracellular domain of NOTCH (ICN) [1,2,[4][5][6].…”

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confidence: 99%

“…The diagnosis of acute panmyelosis with myelofibrosis (APMF) is still not based on genomic changes but on clinicopathologic features and the exclusion of other myeloid malignancies, in particular AML with myelodysplasia-related changes (AML-MRC) [2]. APMF is a rapidly progressive hyperfibrotic subtype of "AML not otherwise specified" (AML NOS) and accounts for <1% of AML cases [3]. This aggressive disease is characterized by rapid onset of cytopenia and constitutional symptoms in the absence of splenomegaly, previous history of myeloproliferative neoplasm (MPN) or myelodysplastic These authors contributed equally: Milena Pantic, Dietmar Pfeifer * Annette Schmitt-Graeff annette.schmitt-graeff@uniklinik-freiburg.de…”

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confidence: 99%

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Diminished interaction between mutant NOTCH1 and the NuRD corepressor complex upregulates CCL17 in chronic lymphocytic leukemia

Wang

Cui

et al. 2019

Leukemia

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NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

Cited by 62 publications

References 181 publications

Next generation cytogenetics: comprehensive assessment of 48 leukemia genomes by genome imaging

Next generation cytogenetics: comprehensive assessment of 48 leukemia genomes by genome imaging

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

Diminished interaction between mutant NOTCH1 and the NuRD corepressor complex upregulates CCL17 in chronic lymphocytic leukemia

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