Review
Oncology
Federico Pozzo, Tamara Bittolo, Erika Tissino, Antonella Zucchetto, Riccardo Bomben, Laura Polcik, Svenja Dannewitz Prosseda, Tanja Nicole Hartmann, Valter Gattei
Summary: This article reviews the mechanisms of activating the NOTCH1 pathway in CLL, including NOTCH1 gene mutations and mutations in other pathways and physiological signals. Understanding the strategies through which CLL cells hijack NOTCH1 signaling is of great importance in designing targeted treatment strategies for CLL management.
Article
Biochemistry & Molecular Biology
Kristan V. Piroeva, Charlotte Mcdonald, Charalampos Xanthopoulos, Chelsea Fox, Christopher T. Clarkson, Jan-Philipp Mallm, Yevhen Vainshtein, Luminita Ruje, Lara C. Klett, Stephan Stilgenbauer, Daniel Mertens, Efterpi Kostareli, Karsten Rippe, Vladimir B. Teif
Summary: This study compared the nucleosome positions in chronic lymphocytic leukemia (CLL) patients and healthy individuals, and found significant changes in nucleosome positioning in CLL. The spacing between nucleosomes was shortened, and changes in nucleosome occupancy were linked to chromatin remodeling and reduced DNA methylation. Nucleosome positioning can be used to classify CLL subtypes and monitor disease progression.
Article
Oncology
Miguel Quijada-Alamo, Claudia Perez-Carretero, Maria Hernandez-Sanchez, Ana-Eugenia Rodriguez-Vicente, Ana-Belen Herrero, Jesus-Maria Hernandez-Sanchez, Marta Martin-Izquierdo, Sandra Santos-Minguez, Monica Del Rey, Teresa Gonzalez, Araceli Rubio-Martinez, Alfonso Garcia de Coca, Julio Davila-Valls, Jose-Angel Hernandez-Rivas, Helen Parker, Jonathan C. Strefford, Rocio Benito, Jose-Luis Ordonez, Jesus-Maria Hernandez-Rivas
Summary: Our study found that concurrent biallelic ATM and TP53 loss is mutually exclusive in CLL, while monoallelic del(11q) and TP53 alterations significantly co-occur in a subset of patients with poor prognosis. CRISPR/Cas9-edited CLL cell lines revealed that combined del(11q) and TP53 mutations provide clonal advantage, whereas CLL cells with biallelic ATM and TP53 loss fail to compete in xenotransplants. Furthermore, CLL cell lines with del(11q) and TP53 mutations show partial responses to B cell receptor signaling inhibitors, indicating potential benefit from ATR inhibition.
CLINICAL AND TRANSLATIONAL MEDICINE
(2021)
Article
Oncology
Katarzyna Skorka, Michal Chojnacki, Marta Masternak, Agnieszka Karczrnarczyk, Edyta Subocz, Ewa Wawrzyniak, Krzysztof Giannopoulos
Summary: NOTCH1(mut) serves as a new prognostic marker in chronic lymphocytic leukaemia (CLL). This study compared droplet digital PCR (ddPCR) and amplification-refractory mutation system PCR (ARMS-PCR) for NOTCH1(mut) assessment in untreated CLL patients. The findings suggest that using ddPCR for detecting NOTCH1(mut) may significantly enhance prognostic stratification in CLL patients.
CANCER MANAGEMENT AND RESEARCH
(2021)
Article
Oncology
Fatima Zahra Jelloul, Richard Yang, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Y. Ok, Sanam Loghavi, Mark J. Routbort, Zhuang Zuo, C. Cameron Yin, Kristen Floyd, Roland L. Bassett, William Wierda, Nitin Jain, Philip Thompson, Rajyalakshmi Luthra, L. Jeffrey Medeiros, Keyur P. Patel
Summary: This study found that both coding and non-coding mutations in the NOTCH1 gene are associated with adverse prognosis in chronic lymphocytic leukemia (CLL) patients. These mutations are more commonly seen in patients without IGVH mutation, ZAP70 positivity, and CD38 positivity, and are associated with shorter time-to-first treatment.
Article
Hematology
Hua-Jay J. Cherng, Raamis Khwaja, Rashmi Kanagal-Shamanna, Guilin Tang, Jan Burger, Philip Thompson, Alessandra Ferrajoli, Zeev Estrov, Koji Sasaki, Deepa Sampath, Xuemei Wang, Hagop Kantarjian, Michael Keating, William G. Wierda, Nitin Jain
Summary: Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL). A retrospective analysis of patients with CLL treated with BTKi was performed, and the results showed that variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] did not significantly influence the efficacy of first-line BTKi, although there was a trend towards shorter progression-free survival (PFS) with increasing karyotypic complexity.
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Review
Oncology
Florence Nguyen-Khac
Summary: Although the 17p deletion is rare in treatment-naive CLL, its frequency is higher in refractory/relapsed CLL, especially in patients undergoing chemotherapy. TP53 disruption is the strongest prognostic factor for chemotherapy resistance, and the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is recommended. Rare cases of CLL may also have translocation or gain of the MYC oncogene, and double-hit CLL (with del(17p) and MYC gain) has a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies needs to be evaluated.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Christian Brieghel, Kathrine Aarup, Mathias H. Torp, Michael A. Andersen, Christina W. Yde, Xin Tian, Adrian Wiestner, Inhye E. Ahn, Carsten U. Niemann
Summary: In chronic lymphocytic leukemia (CLL), patients with multi-hit TP53 aberrations have poorer overall survival, progression-free survival, and time-to-progression compared to those with single-hit TP53, while single-hit TP53 defines a distinct subgroup of patients with excellent response to single-agent ibrutinib. These findings highlight the importance of further investigation into prognostication and management of multi-hit TP53 CLL.
CLINICAL CANCER RESEARCH
(2021)
Review
Oncology
Jennifer Edelmann
Summary: This article reviews the mutations of NOTCH1 in CLL and their impact on disease progression, discusses the effect of NOTCH1 mutations on treatment response, and provides insight into other alterations that may contribute to the dysregulation of NOTCH1 signaling in CLL cells.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Giuseppa De Luca, Giannamaria Cerruti, Sonia Lastraioli, Romana Conte, Adalberto Ibatici, Nikki Di Felice, Fortunato Morabito, Paola Monti, Gilberto Fronza, Serena Matis, Monica Colombo, Sonia Fabris, Alessia Ciarrocchi, Antonino Neri, Paola Menichini, Manlio Ferrarini, Paolo Nozza, Franco Fais, Giovanna Cutrona, Mariella Dono
Summary: The use of Next Generation Sequencing (NGS) in CLL patients revealed a high frequency of subclonal TP53 mutations. Precise identification of these mutations during the disease is necessary to prevent treatment failures.
HEMATOLOGICAL ONCOLOGY
(2022)
Article
Genetics & Heredity
Binyamin A. Knisbacher, Ziao Lin, Cynthia K. Hahn, Ferran Nadeu, Marti Duran-Ferrer, Kristen E. Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Munoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara Lopez-Tamargo, Stacey M. Fernandes, Clare Sun, Mariela Sivina, Laura Z. Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, Francois Aguet, Jan A. Burger, Adrian Wiestner, Thomas J. Kipps, Jennifer R. Brown, Michael Hallek, Chip Stewart, Donna S. Neuberg, Jose Martin-Subero, Xose S. Puente, Stephan Stilgenbauer, Catherine J. Wu, Elias Campo, Gad Getz
Summary: This study identifies genetic drivers and molecular subtypes associated with clinical outcomes in chronic lymphocytic leukemia (CLL) through genomic, transcriptomic, and epigenomic analysis. The findings provide fresh insights into the oncogenesis and prognostication of CLL.
Article
Oncology
Stefano Baldoni, Beatrice Del Papa, Filomena De Falco, Erica Dorillo, Carlo Sorrentino, Chiara Rompietti, Francesco Maria Adamo, Manuel Nogarotto, Debora Cecchini, Elena Mondani, Estevao Carlos Silva Barcelos, Lorenzo Moretti, Maria Grazia Mameli, Bianca Fabi, Daniele Sorcini, Arianna Stella, Raffaella Giancola, Francesco Guardalupi, Francesca Ulbar, Sara Plebani, Valerio Guarente, Emanuela Rosati, Marta Di Nicola, Michele Marchioni, Mauro Di Ianni, Paolo Sportoletti
Summary: This study found that NOTCH1 activation is a negative prognostic factor in chronic lymphocytic leukemia (CLL) patients, significantly reducing Time To First Treatment (TTFT) regardless of NOTCH1 and IGHV mutation status. Activation of NOTCH2 and expression of JAGGED1 also influence clinical outcomes in this group, highlighting the need for further dedicated studies to refine CLL risk stratification using different components of the NOTCH network.
FRONTIERS IN ONCOLOGY
(2021)
Review
Medicine, General & Internal
Maciej Putowski, Krzysztof Giannopoulos
Summary: CLL is highly heterogeneous and may be treated with personalized therapy through targeting new mutations with drugs. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signaling targeting mechanisms include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. Studies have shown that newly discovered mutations and their signaling pathways play key roles in the course of the disease.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Oncology
Thierry Soussi, Panagiotis Baliakas
Summary: Locus-specific databases are essential tools for basic and clinical research. They gather extensive information curated by experts from the literature. TP53 mutation databases play a crucial role in the validation and diagnosis of TP53 variants in chronic lymphocytic leukemia.
FRONTIERS IN ONCOLOGY
(2022)
Article
Hematology
Giovanni Del Poeta, Annalisa Biagi, Luca Laurenti, Annalisa Chiarenza, Federico Pozzo, Idanna Innocenti, Massimiliano Postorino, Francesca Maria Rossi, Maria Ilaria Del Principe, Riccardo Bomben, Paolo de Fabritiis, Antonio Bruno, Maria Cantonetti, Francesco Di Raimondo, Antonella Zucchetto, Valter Gattei
Summary: NOTCH1 mutations are associated with poorer response to ibrutinib treatment in chronic lymphocytic leukemia patients, leading to shorter progression free survival and overall survival.