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
Cell Biology
Damjan Avsec, Marja Skrlj Miklavcic, Tilen Burnik, Masa Kanduser, Marusa Bizjak, Helena Podgornik, Irena Mlinaric-Rascan
Summary: Chronic lymphocytic leukemia (CLL) is a type of hematological cancer involving B lymphocytes, and venetoclax is a commonly used targeted therapy. This study found that certain molecular mechanisms in CLL cells can lead to resistance to venetoclax, but targeting these mechanisms can overcome the resistance.
CELL DEATH & DISEASE
(2022)
Article
Medicine, Research & Experimental
Andrea N. Mazzarello, Eva Gentner-Goebel, Marcus Duehren-von Minden, Tatyana N. Tarasenko, Antonella Nicolo, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R. Rai, Jan A. Burger, Peter J. McGuire, Palash C. Maity, Hassan Jumaa, Nicholas Chiorazzi
Summary: This study found that IgM plays a critical and selective role in BCR signaling and B cell fate decisions in chronic lymphocytic leukemia (CLL), which may open up new avenues for CLL therapy.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
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
Alicia M. Vaca, Nikolaos Ioannou, Mariela Sivina, Elisavet Vlachonikola, Karen Clise-Dwyer, Ekaterina Kim, Dan Li, Qing Ma, Alessandra Ferrajoli, Zeev Estrov, William G. Wierda, Piers E. M. Patten, Alan G. Ramsay, Jan A. Burger
Summary: This study reveals the interaction and clonal expansion mechanism between chronic lymphocytic leukemia (CLL) cells and T-cell subsets, indicating the interaction of Tfh cells with proliferating leukemia cells and providing new avenues for treating CLL.
Article
Hematology
Clare Sun, Chen Yun-Ching, Aina Martinez Zurita, Maria Joao Baptista, Stefania Pittaluga, Delong Liu, Daniel Rosebrock, Satyen Harish Gohil, Nakhle S. Saba, Theresa Davies-Hill, Sarah E. M. Herman, Gad Getz, Mehdi Pirooznia, Catherine J. Wu, Adrian Wiestner
Summary: In CLL, oncogenic processes are upregulated in the lymph nodes and in cases with unmutated IGHV region. Single-cell RNA sequencing reveals 3 major cell states in CLL: quiescent, activated, and proliferating. Activated tumor cells are associated with inferior treatment-free survival and the presence of activated CD4+ memory T cells and M2 macrophages in the lymph nodes. Clonal evolution occurs in approximately half of the patients, but is not associated with AICDA expression. However, a T-cell inflamed microenvironment in the lymph nodes is associated with clonal stability.
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.
Article
Hematology
Sonali Sharma, Gabriela Mladonicka Pavlasova, Vaclav Seda, Katerina Amruz Cerna, Eva Vojackova, Daniel Filip, Laura Ondrisova, Veronika Sandova, Lenka Kostalova, Pedro F. Zeni, Marek Borsky, Jan Oppelt, Kvetoslava Liskova, Leos Kren, Andrea Janikova, Sarka Pospisilova, Stacey M. Fernandes, Medhat Shehata, Laura Z. Rassenti, Ulrich Jaeger, Michael Doubek, Matthew S. Davids, Jennifer R. Brown, Jiri Mayer, Thomas J. Kipps, Marek Mraz
Summary: The study revealed changes in miRNA expression in the CLL microenvironment, with members of the miR-29 family playing a crucial role in BCR signaling and prognosis of CLL patients. TRAF4 was identified as a direct target of miR-29, influencing CLL cell responsiveness to CD40 activation and NF-kappa B signaling. The miR-29-TRAF4-CD40 signaling axis modulated by BCR activity demonstrates a novel regulatory mechanism in CLL.
Article
Biochemistry & Molecular Biology
Alejandro M. Hortal, Clara L. Oeste, Claudia Cifuentes, Miguel Alcoceba, Isabel Fernandez-Pisonero, Laura Clavain, Rut Tercero, Pilar Mendoza, Veronica Dominguez, Marta Garcia-Flores, Belen Pintado, David Abia, Carmen Garcia-Macias, Almudena Navarro-Bailon, Xose R. Bustelo, Marcos Gonzalez, Balbino Alarcon
Summary: The overexpression of wild type RRAS2 is found to be associated with the development of CLL. A single nucleotide polymorphism (rs8570) in the 3'UTR of RRAS2 mRNA is linked to higher expression of RRAS2 and more aggressive disease in CLL. Overexpression of wild type RRAS2 in mice provokes the development of CLL, accompanied by strong convergent selection of somatic mutations. The R-RAS2 protein physically binds to the BCR and mediates BCR signals in CLL.
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)
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
Oncology
Mariela Sivina, Lianchun Xiao, Ekaterina Kim, Alicia Vaca, Shih-Shih Chen, Michael J. Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G. Wierda, Xuelin Huang, Nicholas Chiorazzi, Jan A. Burger
Summary: CXCL13, a chemoattractant, plays a key role in organizing the cellular architecture of B-cell follicles and germinal centers. Elevated CXCL13 plasma concentrations are associated with CLL disease activity and progression, highlighting the importance of the crosstalk between CLL cells and the SLO microenvironment.
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
Liana Nikolaenko, Tingting Liu, Alexey V. Danilov
Summary: The treatment landscape of chronic lymphocytic leukemia (CLL) has been significantly altered with the introduction of novel targeted therapies, including PI3K inhibitors like idelalisib and duvelisib approved for therapy of relapsed/refractory (R/R) CLL. Duvelisib, a selective dual PI3K delta/gamma inhibitor, has shown meaningful efficacy in high-risk R/R CLL patients and may be particularly suitable for those who are suboptimal candidates for BTK inhibitors. Monitoring and managing adverse events is crucial for the continued role of duvelisib in therapy of R/R CLL.
EXPERT REVIEW OF ANTICANCER THERAPY
(2021)
Article
Oncology
Natasha Malik, Jodie Hay, Hassan N. B. Almuhanna, Karen M. Dunn, Jamie Lees, Jennifer Cassels, Jiatian Li, Rinako Nakagawa, Owen J. Sansom, Alison M. Michie
Summary: This study reveals the essential role of mTORC1 in the initiation/maintenance of leukemia in a CLL model and identifies the inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
Review
Oncology
Francesco Forconi, Stuart A. Lanham, Giorgia Chiodin
Summary: This review focuses on the analysis of immunoglobulin in chronic lymphocytic leukemia (CLL) tumor cells and its biological and clinical implications. The analysis of immunoglobulin structure, levels, and signaling characteristics has improved our understanding of CLL and provided insights into its origin, progression, therapy choice, and prognosis. The variability of surface immunoglobulin levels and signaling has an impact on the behavior of CLL, affecting its clinical course and response to treatment.
Article
Hematology
Zhenghao Chen, Helga Simon-Molas, Gaspard Cretenet, Beatriz Valle-Argos, Lindsay D. Smith, Francesco Forconi, Bauke Schomakers, Michel van Weeghel, Dean J. Bryant, Jaco A. C. van Bruggen, Fleur S. Peters, Jeffrey C. Rathmell, Gerritje J. W. van der Windt, Arnon P. Kater, Graham Packham, Eric Eldering
Summary: Through metabolomic and transcriptomic analysis of chronic lymphocytic leukemia (CLL) cells, this study reveals the metabolic differences between cells in the lymph nodes and peripheral blood. The CD40 and BCR signaling pathways play different roles in regulating cell metabolism, which may be related to therapeutic response. Additionally, the significant use of amino acids as fuel for the tricarboxylic acid cycle suggests new therapeutic vulnerabilities.
Article
Cell Biology
Joe Taylor, Sarah Wilmore, Sophie Marriot, Karly-Rai Rogers-Broadway, Rachel Fell, Annabel R. Minton, Tom Branch, Meg Ashton-Key, Mark Coldwell, Freda K. Stevenson, Francesco Forconi, Andrew J. Steele, Graham Packham, Alison Yeomans
Summary: This study provides new insights into the regulation of mRNA translation in B-cell malignancies, highlighting the importance of combining kinase inhibitors to target translation control and MYC expression.
CELLULAR SIGNALLING
(2022)
Article
Hematology
Giorgia Chiodin, Samantha Drennan, Enrica A. Martino, Laura Ondrisova, Isla Henderson, Luis del Rio, Ian Tracy, Annalisa D'Avola, Helen Parker, Silvia Bonfiglio, Lydia Scarfo, Lesley-Ann Sutton, Jonathan C. Strefford, Jade Forster, Oliver Brake, Kathleen N. Potter, Benjamin Sale, Stuart Lanham, Marek Mraz, Paolo Ghia, Freda K. Stevenson, Francesco Forconi
Summary: Chronic lymphocytic leukemia (CLL) cells with high surface IgM (sIgM) levels progress more rapidly and can regain sIgM expression during ibrutinib therapy. High sIgM levels are associated with shorter time to new treatment. Ibrutinib inhibits sIgM-mediated signaling more effectively in CLL cells with low sIgM levels.
Article
Cell Biology
Rachael Arthur, Alexander Wathen, A. Elizabeth Lemm, K. Freda Stevenson, Francesco Forconi, J. Adam Linley, J. Andrew Steele, Graham Packham, Beatriz Valle-Argos
Summary: BTK inhibitors (BTKi) have shown significant improvement in the treatment of chronic lymphocytic leukemia (CLL) and certain forms of B-cell lymphoma. However, the activation of BTK-independent calcium signaling may limit the efficacy of BTKi. Inhibition of SYK or dual inhibition of BTK and RAC may be alternative strategies to enhance pathway blockade.
CELLULAR SIGNALLING
(2022)
Letter
Oncology
Riccardo Moia, Riccardo Dondolin, Maria Stefania De Propris, Donatella Talotta, Samir Mouhssine, Francesca Perutelli, Gianluigi Reda, Veronica Mattiello, Gian Matteo Rigolin, Marina Motta, Jacopo Olivieri, Renato Fanin, Omar Perbellini, Isacco Ferrarini, Francesca Romana Mauro, Ilaria Del Giudice, Luca Laurenti, Annamaria Tomasso, Massimo Gentile, Anna Maria Frustaci, Alessandra Tedeschi, Alessandro Gozzetti, Caterina Stelitano, Carlo Visco, Carol Moreno, Francesco Forconi, Roberto Marasca, Marta Coscia, Davide Rossi, Robin Foa, Gianluca Gaidano
HEMATOLOGICAL ONCOLOGY
(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.
Letter
Medicine, General & Internal
Francesco Forconi, Margaret Ashton-Key, Nicola Meakin
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Oncology
Jack G. Fisher, Amber D. P. Doyle, Lara V. Graham, Shreyanshi Sonar, Ben Sale, Isla Henderson, Luis Del Rio, Peter W. M. Johnson, Yosef Landesman, Mark S. Cragg, Francesco Forconi, Christopher J. Walker, Salim. I. Khakoo, Matthew D. Blunt
Summary: The XPO1 inhibitor selinexor is being investigated in combination with the BTK inhibitor ibrutinib for CLL and non-Hodgkin lymphoma. Selinexor induces apoptosis of tumor cells and modulates NK cell and T cell cytotoxicity against lymphoma cells.
Article
Hematology
Silvia Bonfiglio, Lesley-Ann Sutton, Viktor Ljungstrom, Antonella Capasso, Tatjana Pandzic, Simone Westrom, Hassan Foroughi-Asl, Aron Skaftason, Anna Gellerbring, Anna Lyander, Francesca Gandini, Gianluca Gaidano, Livio Trentin, Lisa Bonello, Gianluigi Reda, Csaba Bodor, Niki Stavroyianni, Constantine S. Tam, Robert Marasca, Francesco Forconi, Pahayiotis Panayiotidis, Ingo Ringshausen, Ozren Kaksic, Anna Maria Frustaci, Sunil Iyengar, Marta Coscia, Stephen P. Mulligan, Loic Ysebaert, Vladimir Strugov, Carolina Pavlovsky, Reneta Walewska, Anders Osterborg, Diego Cortese, Pamela Ranghetti, Panagiotis Baliakas, Kostas Stamatopoulos, Lydia Scarfo, Richard Rosenquist, Paolo Ghia
Summary: In this multicenter retrospective study, researchers found that approximately 65% of relapsed patients and 12% of responding patients with chronic lymphocytic leukemia (CLL) on ibrutinib treatment carried hotspot mutations in the BTK and/or PLCG2 genes. The study also identified a predominance of BRAF and IKZF3 mutations in relapsed patients. These findings suggest the presence of additional mechanisms contributing to resistance in patients failing ibrutinib treatment.
Article
Immunology
Matthew D. Blunt, Andres Vallejo Pulido, Jack G. Fisher, Lara Graham, Amber D. P. Doyle, Rebecca Fulton, Matthew J. Carter, Marta Polak, Peter W. M. Johnson, Mark S. Cragg, Francesco Forconi, Salim Khakoo
Summary: This study demonstrates that KIR2DS2 marks a population of NK cells primed for anticancer activity and is associated with enhanced NK cell-mediated cytotoxicity.
JOURNAL OF IMMUNOLOGY
(2022)