Review
Oncology
Yu Nie, Xiaoya Yun, Ya Zhang, Xin Wang
Summary: Metabolic reprogramming plays a vital role in the initiation and progression of chronic lymphocytic leukemia (CLL). This review summarizes the critical metabolic processes in CLL and discusses the regulation of metabolism by cells in the microenvironment and oncogenes/tumor suppressor regulators. Targeting metabolic enzymes or signal pathways may impede the progression of CLL.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Oncology
Matthew G. Cyr, Maissa Mhibik, Junpeng Qi, Haiyong Peng, Jing Chang, Erika M. Gaglione, David Eik, John Herrick, Thomas Venables, Scott J. Novick, Valentine V. Courouble, Patrick R. Griffin, Adrian Wiestner, Christoph Rader
Summary: This study identified highly potent and specific anti-Siglec-6 antibodies that can effectively target and kill Siglec-6(+) leukemic and healthy B cells, while sparing Siglec-6(-) healthy B cells. The T-biAb RC-1 demonstrated the best therapeutic efficacy, eliminating CLL cells at very low ratios and also showing toxicity against healthy B cells. These findings suggest Siglec-6 as a unique target for CLL treatment.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Oncology
Thomas A. Burley, Emma Kennedy, Georgia Broad, Melanie Boyd, David Li, Timothy Woo, Christopher West, Eleni E. Ladikou, Iona Ashworth, Christopher Fegan, Rosalynd Johnston, Simon Mitchell, Simon P. Mackay, Andrea G. S. Pepper, Chris Pepper
Summary: In this study, the researchers evaluated the effects of an NF-kappa B inducing kinase (NIK) inhibitor, CW15337, on primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines, and normal B- and T-lymphocytes. They found that CW15337 induced apoptosis and inhibited the non-canonical NF-kappa B signaling pathway, reversing BCL2 family-mediated resistance. The combination of CW15337 with fludarabine or ABT-199 showed synergistic cytotoxic effects.
Article
Medicine, Research & Experimental
Zhangdi Xu, Bihui Pan, Yi Miao, Yue Li, Shuchao Qin, Jinhua Liang, Yilin Kong, Xinyu Zhang, Jing Tang, Yi Xia, Huayuan Zhu, Li Wang, Jianyong Li, Jiazhu Wu, Wei Xu
Summary: This study aimed to investigate the prognostic role of XPO1 and the therapeutic effect of Selinexor in chronic lymphocytic leukemia (CLL). The results showed that XPO1 was highly expressed in CLL patients and was associated with poor prognosis. Selinexor, an inhibitor of XPO1, induced apoptosis in CLL cells and had inhibitory effects on cell proliferation and cell cycle progression. Downregulation of NF-kappa B and FOXO pathways was observed in CLL cells treated with Selinexor.
CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Audrey L. Smith, Alexandria P. Eiken, Sydney A. Skupa, Dalia Y. Moore, Lelisse T. Umeta, Lynette M. Smith, Elizabeth R. Lyden, Christopher R. D'Angelo, Avyakta Kallam, Julie M. Vose, Tatiana G. Kutateladze, Dalia El-Gamal
Summary: This study demonstrates the preclinical efficacy of SRX3305, a novel inhibitor, in chronic lymphocytic leukemia (CLL). SRX3305 can target multiple disease-driving factors in CLL, inhibiting cell proliferation and migration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Hematology
Rebecka Svanberg, Sine Janum, Piers E. M. Patten, Alan G. Ramsay, Carsten U. Niemann
Summary: The tumor microenvironment plays a crucial role in the development and survival of malignant B-cell clones in chronic lymphocytic leukemia. Therapeutic strategies targeting the interactions within the microenvironment may significantly impact clinical efficacy. Understanding the effects of current therapeutic agents on microenvironmental cells and interactions can guide and improve CLL treatment strategies.
Article
Multidisciplinary Sciences
Elena Cesaro, Andrea Patrizia Falanga, Rosa Catapano, Francesca Greco, Simona Romano, Nicola Borbone, Arianna Pastore, Maria Marzano, Federico Chiurazzi, Stefano D'Errico, Gennaro Piccialli, Giorgia Oliviero, Paola Costanzo, Michela Grosso
Summary: In this study, we successfully downregulated the expression of CD5 in chronic lymphocytic leukemia using an innovative antisense approach based on Peptide Nucleic Acids. The results suggest that anti-CD5 PNAs could be potential therapeutics for CLL.
Article
Hematology
Fabienne Meier-Abt, Junyan Lu, Ester Cannizzaro, Marcel F. Pohly, Sandra Kummer, Sibylle Pfammatter, Laura Kunz, Ben C. Collins, Ferran Nadeu, Kwang Seok Lee, Peng Xue, Myriam Gwerder, Michael Roiss, Jennifer Huellein, Sebastian Scheinost, Sascha Dietrich, Elias Campo, Wolfgang Huber, Ruedi Aebersold, Thorsten Zenz
Summary: This study uncovered mutations affecting protein expression in CLL and identified signaling pathways associated with trisomy 12. STAT2 protein expression was linked to specific drug responses, providing a protein expression reference map for CLL.
Review
Oncology
Ilenia Sana, Maria Elena Mantione, Piera Angelillo, Marta Muzio
Summary: In recent years, significant progress has been made in the clinical management of chronic lymphocytic leukemia and other B-cell malignancies by targeting B-cell receptor signaling molecules. However, a proportion of patients remain uncured, leading to efforts in studying new potential targets. NFAT is overexpressed and constitutively activated in CLL, with targeting this molecule impacting on CLL cell viability.
FRONTIERS IN ONCOLOGY
(2021)
Article
Hematology
Freda K. Stevenson, Francesco Forconi, Thomas J. Kipps
Summary: Research into chronic lymphocytic leukemia has led to significant improvements in the assessment and treatment of patients, with designer drugs now successfully targeting tumor cells based on their biology. Classifying CLL into unmutated (U) and mutated (M) diseases based on the mutational status of IGHV sequences reveals distinct origins, biology, and clinical behaviors for each. Despite advances, challenges such as cell-escape strategies and immunosuppression remain, necessitating continued research into CLL biology.
Article
Oncology
Cedric Schleiss, Raphael Carapito, Luc-Matthieu Fornecker, Leslie Muller, Nicodeme Paul, Ouria Tahar, Angelique Pichot, Manuela Tavian, Alina Nicolae, Laurent Miguet, Laurent Mauvieux, Raoul Herbrecht, Sarah Cianferani, Jean-Noel Freund, Christine Carapito, Myriam Maumy-Bertrand, Seiamak Bahram, Frederic Bertrand, Laurent Vallat
Summary: The study reveals a proliferative genetic program activated by BCR in primary leukemic cells, consisting of 430 genes and 374 proteins. Mathematical modeling highlights a transcriptional network associated with cell proliferation.
Review
Oncology
Elisavet Vlachonikola, Kostas Stamatopoulos, Anastasia Chatzidimitriou
Summary: The treatment of chronic lymphocytic leukemia (CLL) is continuously evolving, with immunotherapy emerging as a therapeutic option to boost immune responses against tumors. However, not all patients benefit from this approach, partly due to dysfunctional T cells in CLL. The tumor microenvironment (TME) is also crucial in impacting immune responses and tumor growth, highlighting the importance of understanding T cell defects and finding ways to overcome them for effective immunotherapy in CLL.
Article
Oncology
Michael Asger Andersen, Klaus Rostgaard, Carsten Utoft Niemann, Henrik Hjalgrim
Summary: The study found that CLL patients have increased susceptibility to infections for decades before diagnosis, and a similar pattern was observed in the offspring of CLL patients. The duration of this time window is consistent with immune dysfunction and/or certain infections playing a causal role in CLL pathogenesis, potentially mediating the association between constitutional infection susceptibility and CLL risk.
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.
Review
Hematology
Sigrid S. Skanland, Anthony R. Mato
Summary: Insight into the mechanisms of resistance to targeted therapies in chronic lymphocytic leukemia (CLL) has led to the development of strategies to prevent and overcome resistance, including combination therapies targeting bypass mechanisms, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. These approaches aim to secure effective treatment options at the relapsed setting and overcome acquired resistance to existing therapies.
Article
Oncology
Maria Elena Mantione, Ilenia Sana, Maria Giovanna Vilia, Michela Riba, Claudio Doglioni, Alessandro Larcher, Umberto Capitanio, Marta Muzio
Summary: Renal cell carcinoma shows a specific pattern of inflammatory receptor expression, with a downregulation of SIGIRR. IL1 stimulation activates the inflammatory pathway in ccRCC cells and induces the expression of various pro-tumor genes. Manipulating this pathway may be beneficial for ccRCC treatment.
FRONTIERS IN ONCOLOGY
(2022)
Editorial Material
Hematology
Lydia Scarfo, Antonio Cuneo
Letter
Hematology
Elisa ten Hacken, Shanye Yin, Robert Redd, Maria Hernandez Sanchez, Kendell Clement, Gabriela Brunsting Hoffmann, Fara F. Regis, Elizabeth Witten, Shuqiang Li, Donna Neuberg, Luca Pinello, Kenneth J. Livak, Catherine J. Wu
Article
Oncology
John N. Allan, Ian W. Flinn, Tanya Siddiqi, Paolo Ghia, Constantine S. Tam, Thomas J. Kipps, Paul M. Barr, Anna Elinder Camburn, Alessandra Tedeschi, Xavier C. Badoux, Ryan Jacobs, Bryone J. Kuss, Livio Trentin, Cathy Zhou, Anita Szoke, Christopher Abbazio, William G. Wierda
Summary: The CAPTIVATE study demonstrates that fixed-duration ibrutinib plus venetoclax is effective in controlling chronic lymphocytic leukemia, including patients with high-risk genomic features. This treatment provides durable progression-free survival and similar overall survival rates.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Jennifer A. Woyach, Paolo Ghia, John C. Byrd, Inhye E. Ahn, Carol Moreno, Susan M. O'Brien, Daniel Jones, Leo W. K. Cheung, Elizabeth Chong, Kevin Kwei, James P. Dean, Danelle F. James, Adrian Wiestner
Summary: Acquired mutations in BTK or PLCG2 genes are associated with clinical progressive disease in CLL patients. Mutations in these genes are rare in previously untreated patients but more common in relapsed/refractory CLL patients. Time to detection of BTK mutations is longer in relapsed/refractory CLL patients.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Dean Bryant, Lindsay Smith, Karly Rai Rogers-Broadway, Laura Karydis, Jeongmin Woo, Matthew D. Blunt, Francesco Forconi, Freda K. Stevenson, Christopher Goodnow, Amanda Russell, Peter Humburg, Graham Packham, Andrew J. Steele, Jonathan C. Strefford
Summary: Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes, with differences in clinical behaviors, B cell receptor (BCR) signaling capacity, and transcriptional profiles. Through mRNA/miRNA sequencing of 38 CLL cases, researchers identified differentially expressed mRNAs and miRNAs between U-CLL and M-CLL, as well as potential regulatory roles of the 14q32 miRNA locus in CLL-related gene regulation and BCR signaling.
Article
Hematology
Carol Moreno, Isabelle G. Solman, Constantine S. Tam, Andrew Grigg, Lydia Scarfo, Thomas J. Kipps, Srimathi Srinivasan, Raghuveer Singh Mali, Cathy Zhou, James P. Dean, Edith Szafer-Glusman, Michael Choi
Summary: This study evaluated immune cell subsets in patients with CLL who received different treatments. The results demonstrated successful elimination of CLL cells and restoration of normal immune cells in some patients.
Article
Hematology
Andrea Visentin, Thomas Chatzikonstantinou, Lydia Scarfo, Anargyros Kapetanakis, Christos Demosthenous, Georgios Karakatsoulis
Summary: In this retrospective international multicenter study, the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders infected by SARS-CoV-2 were described. The study also investigated the development of post-COVID condition. The data showed that patients infected in the most recent phases of the pandemic had lower hospitalization rates, ICU admission rates, and mortality compared to those infected in the initial phases. Overall survival improved throughout the phases. Age, comorbidity, and CLL-directed treatment were identified as risk factors for mortality. A significant number of patients developed post-COVID condition, characterized by fatigue, dyspnea, lasting cough, and impaired concentration. The severity of infection was the only risk factor for developing post-COVID. Further investigations are warranted to understand the impact of COVID-19 on CLL patients.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Hematology
John F. Seymour, John C. Byrd, Paolo Ghia, Arnon P. Kater, Asher Chanan-Khan, Richard R. Furman, Susan O'Brien, Jennifer R. Brown, Talha Munir, Anthony Mato, Stephan Stilgenbauer, Naghmana Bajwa, Paulo Miranda, Kara Higgins, Ellie John, Marianne de Borja, Wojciech Jurczak, Jennifer A. Woyach
Summary: ELEVATE-RR trial showed that acalabrutinib has noninferior progression-free survival and lower incidence of key adverse events compared to ibrutinib in previously treated chronic lymphocytic leukemia patients. Post hoc analysis further characterized the adverse events of acalabrutinib and ibrutinib. It was found that acalabrutinib had higher incidence rates of headache and cough, while ibrutinib had higher rates of diarrhea, joint pain, urinary tract infection, back pain, muscle spasms, and dyspepsia. Ibrutinib also had higher rates of atrial fibrillation/flutter, hypertension, and bleeding. The discontinuation rate due to adverse events was lower with acalabrutinib. The overall event-based analyses and adverse event burden scores demonstrated that ibrutinib had a higher burden of adverse events compared to acalabrutinib, particularly in atrial fibrillation, hypertension, and bleeding.
Article
Oncology
Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfo, Lucia Tognolo, Maria Pia Ballardini, Antonio Urso, Mariarosaria Sessa, Silvia Gambara, Francesca Cura, Monica Fortini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo
Summary: This analysis evaluates the effectiveness of first-line ibrutinib in 747 CLL patients with TP53 aberrations. The study found a treatment persistence rate of 63.4% and a survival rate of 82.6% at 24 months. Disease progression or death were the main reasons for treatment discontinuation. The study also identified factors associated with an increased risk of discontinuation and death.
BLOOD CANCER JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Miriam Meloni, Ilenia Sana, Maria Elena Mantione, Michela Riba, Marta Muzio
Summary: This study analyzed the expression profiles of different leukemia cell lines before and after CpG stimulation. The results identified NFKBIZ mRNA and IkBz protein as robust markers of TLR9 activation in MEC2 and PCL12 cell lines, but not in HG3 cells. Comparison with patient samples indicated that MEC2 more closely resembled patient cells in terms of TLR responsiveness, with high levels of IkBz expression and fewer regulated genes.
Article
Hematology
Marta Sampietro, Valeria Cassina, Domenico Salerno, Federica Barbaglio, Enrico Buglione, Claudia Adriana Marrano, Riccardo Campanile, Lydia Scarfo, Doreen Biedenweg, Bob Fregin, Moreno Zamai, Alfonsa Diaz Torres, Veronica Labrador Cantarero, Paolo Ghia, Oliver Otto, Francesco Mantegazza, Valeria R. Caiolfa, Cristina Scielzo
Summary: Chronic lymphocytic leukemia (CLL) is a disease with intense trafficking of leukemic cells between the blood and lymphoid tissues. The behavior of CLL cells differs from healthy B cells in terms of their cytoskeleton rearrangement and response to external cues. By using advanced microscopy and nanomechanical approaches, it was found that CLL cells possess specific actomyosin organization and altered mechanical properties. Treatment with Bruton's tyrosine kinase inhibitors restored the CLL cells' mechanical properties and activated the actomyosin complex, suggesting a potential therapeutic target for drug resistance in CLL.
Article
Oncology
Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A. Redd, Neil Ruthen, Sebastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M. Parry, Julien Broseus, Romain Guieze, Fabienne Lucas, Maria Hernandez-Sanchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D. Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A. Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S. Davids, Gad Getz, Kenneth J. Livak, Ivana Bozic, Donna S. Neuberg, Ruben D. Carrasco, Catherine J. Wu
Summary: Using CRISPR-Cas9 editing in mice, researchers simulated the transformation of chronic lymphocytic leukemia (CLL) into large cell lymphoma and uncovered the role of key gene mutations.
BLOOD CANCER DISCOVERY
(2023)