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
Andrea N. Mazzarello, Mark Fitch, Martina Cardillo, Anita Ng, Sabreen Bhuiya, Esha Sharma, Davide Bagnara, Jonathan E. Kolitz, Jacqueline C. Barrientos, Steven L. Allen, Kanti R. Rai, Joanna Rhodes, Marc K. Hellerstein, Nicholas Chiorazzi
Summary: Chronic lymphocytic leukemia (CLL) clones contain subpopulations with different ages and phenotypes. The youngest cells are recently born and proliferative, while the oldest cells are resting. Cells with high levels of surface membrane proteins are younger, and stimulation through these proteins results in a phenotype consistent with in vivo observations. Older cells are less sensitive to drug inhibition.
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
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.
Review
Oncology
Laura Patrussi, Nagaja Capitani, Cosima T. Baldari
Summary: IL-9, a soluble factor secreted by immune cells, has been found in several tumor niches, with dual roles in promoting or counteracting tumor development depending on the specific type of cancer. Recent studies implicate IL-9 in chronic lymphocytic leukemia pathogenesis, yet the molecular mechanisms remain unclear.
Review
Cell Biology
Stefania Fiorcari, Rossana Maffei, Claudio Giacinto Atene, Leonardo Potenza, Mario Luppi, Roberto Marasca
Summary: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, involving cooperation between genetic defects and tumor microenvironmental interactions in pathogenesis. CLL is considered addicted to the host, with crosstalk between leukemic cells and the tumor microenvironment essential for supporting CLL cell survival and proliferation.
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
Multidisciplinary Sciences
Zachary A. Hing, Janek S. Walker, Ethan C. Whipp, Lindsey Brinton, Matthew Cannon, Pu Zhang, Steven Sher, Casey B. Cempre, Fiona Brown, Porsha L. Smith, Claudio Agostinelli, Stefano A. Pileri, Jordan N. Skinner, Katie Williams, Hannah Phillips, Jami Shaffer, Larry P. Beaver, Alexander Pan, Kyle Shin, Charles T. Gregory, Gulcin H. Ozer, Selen A. Yilmaz, Bonnie K. Harrington, Amy M. Lehman, Lianbo Yu, Vincenzo Coppola, Pearlly Yan, Peggy Scherle, Min Wang, Philip Pitis, Chaoyi Xu, Kris Vaddi, Selina Chen-Kiang, Jennifer Woyach, James S. Blachly, Lapo Alinari, Yiping Yang, John C. Byrd, Robert A. Baiocchi, Bradley W. Blaser, Rosa Lapalombella
Summary: PRMT5 plays an important role in the progression of CLL to Richter transformation, and the PRMT5 inhibitor PRT382 shows potential therapeutic value.
NATURE COMMUNICATIONS
(2023)
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
Biochemistry & Molecular Biology
Yin Yang, Li Liu, Haley O. Tucker
Summary: This study reveals that STYK1/NOK can induce immunosuppressive B-CLL-like disease in transgenic mice, resulting in shorter lifespan. The phenotype of STYK1/NOK-induced B-CLL is heterogeneous, with lymphadenectasis and hepatomegaly and/or splenomegaly commonly observed. Additionally, STYK1/NOK-tg mice show reduced immune responses. The upregulation of STYK1/NOK is also observed in primary human B-CLL.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Medicine, General & Internal
Barbara Eichhorst, Carsten U. Niemann, Arnon P. Kater, Moritz Fuerstenau, Julia von Tresckow, Can Zhang, Sandra Robrecht, Michael Gregor, Gunnar Juliusson, Patrick Thornton, Philipp B. Staber, Tamar Tadmor, Vesa Lindstrom, Caspar da Cunha-Bang, Christof Schneider, Christian B. Poulsen, Thomas Illmer, Bjoern Schoettker, Thomas Noesslinger, Ann Janssens, Ilse Christiansen, Michael Baumann, Henrik Frederiksen, Marjolein van der Klift, Ulrich Jaeger, Maria B. L. Leys, Mels Hoogendoorn, Kourosh Lotfi, Holger Hebart, Tobias Gaska, Harry Koene, Lisbeth Enggaard, Jereon Goede, Josien C. Regelink, Anouk Widmer, Florian Simon, Nisha De Silva, Anna-Maria Fink, Jasmin Bahlo, Kirsten Fischer, Clemens-Martin Wendtner, Karl A. Kreuzer, Matthias Ritgen, Monika Brueggemann, Eugen Tausch, Mark-David Levin, Marinus van Oers, Christian Geisler, Stephan Stilgenbauer, Michael Hallek
Summary: In fit patients with CLL, venetoclax-obinutuzumab, with or without ibrutinib, showed superior results compared to chemoimmunotherapy as a first-line treatment, with higher rates of undetectable minimal residual disease and progression-free survival.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Oncology
David E. Spaner, Tina YuXuan Luo, Guizhi Wang, Gideon Schreiber, Daniel Harari, Yonghong Shi
Summary: The study investigated the effect of ruxolitinib on CLL cells and found that it increased IRAK4 phosphorylation, enhanced p38 and NFKB1 phosphorylation, and reduced STAT3 phosphorylation. High levels of IL-10 contributed to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL-10 transcription and reduced IL-10 production. The study suggests that targeting growth factors with JAK inhibitors in CLL may have negative effects on tumor suppressors like IL-10. Specific inhibition of growth-promoting cytokines or infusion of suppressive cytokines like IL-10 might be better strategies for manipulating cytokines in CLL.
FRONTIERS IN ONCOLOGY
(2023)
Article
Medicine, Research & Experimental
Andres Chang, Anton M. Sholukh, Andreas Wieland, David L. Jaye, Mary Carrington, Meei-Li Huang, Hong Xie, Keith R. Jerome, Pavitra Roychoudhury, Alexander L. Greninger, Jean L. Koff, Jonathon B. Cohen, David M. Koelle, Lawrence Corey, Christopher R. Flowers, Rafi Ahmed
Summary: Herpes simplex virus lymphadenitis (HSVL) is a rare presentation in patients with chronic lymphocytic leukemia (CLL), characterized by systemic symptoms and absence of herpetic lesions. The study found that HSV-specific immune responses during HSVL may contribute to decreased CLL tumor burden.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Immunology
Yu-Chen Enya Chen, Melinda Burgess, Sally Mapp, Peter Mollee, Devinder Gill, Antje Blumenthal, Nicholas A. Saunders
Summary: The study reveals that the SIRP alpha axis suppresses ADP responses to the anti-CD20 antibody by NLCs derived from CLL patients, and further demonstrates that this innate immune checkpoint contributes to resistance through the regulation of the Shp1-mediated pathway.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Hematology
Emma Kennedy, Eve Coulter, Emma Halliwell, Nuria Profitos-Peleja, Elisabeth Walsby, Barnaby Clark, Elizabeth H. Phillips, Thomas A. Burley, Simon Mitchell, Stephen Devereux, Christopher D. Fegan, Christopher Jones, Rosalynd Johnston, Tim Chevassut, Ralph Schulz, Martina Seiffert, Angelo Agathanggelou, Ceri Oldreive, Nicholas Davies, Tatjana Stankovic, Triantafillos Liloglou, Chris Pepper, Andrea G. S. Pepper
Summary: Despite the advancements in B-cell receptor-targeted inhibitors, CLL remains incurable. TLR9 activation by unmethylated DNA is associated with disease progression in CLL. High TLR9 expression promotes CLL cell migration and disease progression, while dual targeting of TLR9 and BTK shows strong synergism as a potential treatment strategy for this incurable disease.
Article
Oncology
Kotryna Seip, Kjetil Jorgensen, Marco Vincent Haselager, Marco Albrecht, Mads Haugland Haugen, Eivind Valen Egeland, Philippe Lucarelli, Olav Engebraaten, Thomas Sauter, Gunhild Mari Maelandsmo, Lina Prasmickaite
Article
Hematology
Marco Haselager, Karoline Kielbassa, Johanna ter Burg, Danique J. C. Bax, Stacey M. Fernandes, Jannie Borst, Constantine Tam, Francesco Forconi, Giorgia Chiodin, Jennifer R. Brown, Julie Dubois, Arnon P. Kater, Eric Eldering
Article
Biochemistry & Molecular Biology
Marco Haselager, Rachel Thijssen, Christopher West, Louise Young, Roel Van Kampen, Elaine Willmore, Simon Mackay, Arnon Kater, Eric Eldering
Summary: In chronic lymphocytic leukemia, signaling via NF-kappa B, particularly through CD40 stimulation, plays a crucial role in driving the expression of anti-apoptotic regulator Bcl-XL. The canonical NF-kappa B pathway first induces Bcl-XL expression, followed by the non-canonical NF-kappa B signaling which boosts and sustains it. This study highlights the potential of selectively targeting the non-canonical NF-kappa B pathway to sensitize venetoclax-resistant CLL cells to apoptosis.
CELL DEATH AND DIFFERENTIATION
(2021)
Review
Immunology
Marco V. Haselager, Eric Eldering
Summary: This review provides an overview of the role of NF-kappa B-inducing kinase (NIK) in non-canonical NF-kappa B signaling and its association with various malignancies. It discusses the current research on NIK activation, stability, and its potential as a therapeutic target for B cell malignancies. The review also compares different inhibitors targeting NIK and emphasizes the need for further in vitro and in vivo studies as well as clinical trials with NIK inhibitors.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Marco V. V. Haselager, Rachel Thijssen, Danique Bax, Demi Both, Francien De Boer, Simon Mackay, Julie Dubois, Clemens Mellink, Arnon P. P. Kater, Eric Eldering
Summary: Resistance to venetoclax, a Bcl-2 inhibitor, is a significant problem in CLL patients. The upregulation of Bcl-2 through signaling pathways in the tumor microenvironment contributes to this resistance. T cells can drive resistance through CD40 and non-canonical NF-kappa B activation. The cytokines IL-21 and IL-4 from T cells differentially affect Bcl-XL expression and sensitivity to venetoclax. Mechanistic studies revealed the role of JAK-STAT signaling and NF-kappa B in regulating Bcl-XL expression, providing potential therapeutic targets for overcoming venetoclax resistance.
MOLECULAR ONCOLOGY
(2023)