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52. KZF-L162R Mutation Affects Splenic Mature B Cell Development and Alters Expression of Aiolos Target Genes

Author

Lazarian, Gregory, primary, Yin, Shanye, additional, Font-tello, Alba, additional, Ten Hacken, Elisa, additional, Sevastianik, Tomasz, additional, Tom, Daniel, additional, Regis, Fara Faye, additional, Gill, Amy, additional, Zheng, Mei, additional, Georgopoulos, Katia, additional, Neuberg, Donna S, additional, Wang, Lili, additional, Carrasco, Ruben D., additional, and Wu, Catherine J., additional

Published
2018
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53. Integrated Genomic and Proteomic Analysis of Murine CLL-like Cells Reveals SF3B1 Mutation to Impact DNA Damage Response and BCR Signaling

Author

Wang, Lili, primary, Yin, Shanye, additional, Martinez, Aina zurita, additional, Regis, Fara Faye, additional, Brooks, Angela, additional, Herman, Sarah E. M., additional, Ten Hacken, Elisa, additional, Obeng, Esther, additional, Campagna, Dean, additional, Fleming, Mark D., additional, Ebert, Benjamin L., additional, Wiestner, Adrian, additional, Leshchiner, Ignaty, additional, Getz, Gad, additional, Carrasco, Ruben D., additional, and Wu, Catherine J., additional

Published
2018
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54. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

Author

Tissino, Erika, primary, Benedetti, Dania, additional, Herman, Sarah E.M., additional, ten Hacken, Elisa, additional, Ahn, Inhye E., additional, Chaffee, Kari G., additional, Rossi, Francesca Maria, additional, Dal Bo, Michele, additional, Bulian, Pietro, additional, Bomben, Riccardo, additional, Bayer, Elisabeth, additional, Härzschel, Andrea, additional, Gutjahr, Julia Christine, additional, Postorino, Massimiliano, additional, Santinelli, Enrico, additional, Ayed, Ayed, additional, Zaja, Francesco, additional, Chiarenza, Annalisa, additional, Pozzato, Gabriele, additional, Chigaev, Alexandre, additional, Sklar, Larry A., additional, Burger, Jan A., additional, Ferrajoli, Alessandra, additional, Shanafelt, Tait D., additional, Wiestner, Adrian, additional, Del Poeta, Giovanni, additional, Hartmann, Tanja Nicole, additional, Gattei, Valter, additional, and Zucchetto, Antonella, additional

Published
2018
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58. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics.

Author

Vitale, Candida, Vitale, Candida, Falchi, Lorenzo, Ten Hacken, Elisa, Gao, Hui, Shaim, Hila, Van Roosbroeck, Katrien, Calin, George, O'Brien, Susan, Faderl, Stefan, Wang, Xuemei, Wierda, William G, Rezvani, Katayoun, Reuben, James M, Burger, Jan A, Keating, Michael J, Ferrajoli, Alessandra, Vitale, Candida, Vitale, Candida, Falchi, Lorenzo, Ten Hacken, Elisa, Gao, Hui, Shaim, Hila, Van Roosbroeck, Katrien, Calin, George, O'Brien, Susan, Faderl, Stefan, Wang, Xuemei, Wierda, William G, Rezvani, Katayoun, Reuben, James M, Burger, Jan A, Keating, Michael J, and Ferrajoli, Alessandra

Abstract

PurposeWe evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.Experimental designThirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3-6, and once every other course during courses 7-24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.ResultsThe overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.ConclusionsThe combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359-67. ©2016 AACR.

Published
2016

59. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics

Author

Vitale, Candida, primary, Falchi, Lorenzo, additional, ten Hacken, Elisa, additional, Gao, Hui, additional, Shaim, Hila, additional, Van Roosbroeck, Katrien, additional, Calin, George, additional, O'Brien, Susan, additional, Faderl, Stefan, additional, Wang, Xuemei, additional, Wierda, William G., additional, Rezvani, Katayoun, additional, Reuben, James M., additional, Burger, Jan A., additional, Keating, Michael J., additional, and Ferrajoli, Alessandra, additional

Published
2016
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61. IgM and IgD Receptors Differentially Contribute to CLL Survival and Chemokine Secretion: Implications for CLL Biology and Treatment

Author

ten Hacken, Elisa, primary, Sivina, Mariela, additional, Ping, Li, additional, O'Brien, Susan, additional, Wierda, William G., additional, Ferrajoli, Alessandra, additional, Estrov, Zeev, additional, Keating, Michael J., additional, Scielzo, Cristina, additional, Ghia, Paolo, additional, Caligaris-Cappio, Federico, additional, and Burger, Jan A., additional

Published
2015
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62. Identification of B Cell Receptor Antigens in the Chronic Lymphocytic Leukemia Microenvironment

Author

ten Hacken, Elisa, primary, Oellerich, Thomas, additional, Gounari, Maria, additional, Hoellenriegel, Julia, additional, Pan, Kuan-Ting, additional, O'Brien, Susan, additional, Wierda, William, additional, Ferrajoli, Alessandra, additional, Estrov, Zeev, additional, Keating, Michael J., additional, Urlaub, Henning, additional, Ghia, Paolo, additional, and Burger, Jan A., additional

Published
2015
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63. Ibrutinib Targets Nurse-like Cells Supporting an Immunosuppressive Phenotype in Chronic Lymphocytic Leukemia

Author

Fiorcari, Stefania, primary, Maffei, Rossana, additional, Audrito, Valentina, additional, Martinelli, Silvia, additional, Ten Hacken, Elisa, additional, Grisendi, Giulia, additional, Zucchini, Patrizia, additional, Quadrelli, Chiara, additional, Luppi, Mario, additional, Burger, Jan A., additional, Deaglio, Silvia, additional, and Marasca, Roberto, additional

Published
2015
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64. Correlation Between Clinical Responses and Immune Characteristics in Patients with Relapsed CLL Treated with Ofatumumab and Lenalidomide

Author

Vitale, Candida, primary, Falchi, Lorenzo, additional, ten Hacken, Elisa, additional, Gao, Hui, additional, Shaim, Hila, additional, Van Roosbroeck, Katrien, additional, Calin, George, additional, O'Brien, Susan, additional, Faderl, Stefan, additional, Wang, Xuemei, additional, Wierda, William, additional, Rezvani, Katayoun, additional, Reuben, James M, additional, Burger, Jan A., additional, Keating, Michael, additional, and Ferrajoli, Alessandra, additional

Published
2015
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66. Splicing Modulation Perturbs Key Survival Pathways and Sensitizes Chronic Lymphocytic Leukemia to Venetoclax Treatment

Author

Ten Hacken, Elisa, Valentin, Rebecca, Sun, Jing, Deng, Jing, Brooks, Angela, Werner, Lillian, Regis, Fara Faye, Gruber, Michaela, Wong, Jessica, Cartun, Zachary, Seiler, Michael, Smith, Peter, Thomas, Michael, Buonamici, Silvia, Ghia, Emanuela M., Kim, Ekaterina, Rassenti, Laura Z., Burger, Jan A., Kipps, Thomas J., Meyerson, Matthew, Neuberg, Donna S., Carrasco, Ruben D., Wang, Lili, Davids, Matthew S., Letai, Anthony, and Wu, Catherine J.

Published
2017
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68. Immunoglobulin Heavy Chain (IgH) Knockout Inhibits Proliferation of Pre-BCR+ B-Cell Acute Lymphoblastic Leukemia (B-ALL) Via a FOXO1 and MYC Dependent Mechanism

Author

Koehrer, Stefan, primary, Havranek, Ondrej, additional, Davis, R Eric, additional, Seyfried, Felix, additional, Coffey, Greg, additional, Kim, Ekaterina, additional, Rosin, Nathalie Y., additional, ten Hacken, Elisa, additional, Jäger, Ulrich, additional, Vanura, Katrina, additional, O'Brien, Susan, additional, Thomas, Deborah A., additional, Kantarjian, Hagop M., additional, Ghosh, Dipanjan, additional, Wang, Zhiqiang, additional, Meyer, Lüder Hinrich, additional, Jumaa, Hassan, additional, and Burger, Jan A., additional

Published
2014
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70. Targeting the LYN/HS1 Signaling Axis in Chronic Lymphocytic Leukemia

Author

ten Hacken, Elisa, primary, Scielzo, Cristina, additional, Betilaccio, Maria Teresa Sabrina, additional, Scarfò, Lydia, additional, Apollonio, Benedetta, additional, Ponzoni, Maurilio, additional, Stamatopoulos, Kostas, additional, Ghia, Paolo, additional, and Caligaris-Cappio, Federico, additional

Published
2012
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71. Targeting B Cell Anergy in Chronic Lymphocytic Leukemia

Author

Apollonio, Benedetta, primary, Scielzo, Cristina, additional, Bertilaccio, Maria Teresa Sabrina, additional, ten Hacken, Elisa, additional, Scarfò, Lydia, additional, Ghia, Paolo, additional, Muzio, Marta, additional, and Caligaris-Cappio, Federico, additional

Published
2012
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73. RPS15and TP53Co-Mutation Drives B Cell Malignancy through Altered Translation and MYC Activation in a Murine Model

Author

Gutierrez, Catherine, Ouspenskaia, Tamara, Fu, Doris, Waddicor, Peyton, Biran, Anat, Liani, Aviv, Lazarian, Gregory, Ten Hacken, Elisa, Witten, Elizabeth, Regis, Fara Faye, Joyal, Heather, Billington, Leah, Lucas, Fabienne, Zheng, Mei, Tye, Blake, Hernandez-Sanchez, Maria, Quijada Álamo, Miguel, Li, Shuqiang, Knisbacher, Binyamin A., Lin, Ziao, Al'Khafaji, Aziz, Wang, Lili, Livak, Kenneth J., Neuberg, Donna S., Cymbalista, Florence, Getz, Gad, Churchman, Stirling, Carrasco, Ruben D., Shao, Sichen, Regev, Aviv, and Wu, Catherine J.

Abstract

Amongst the novel putative drivers identified by large-scale sequencing studies of chronic lymphocytic leukemia (CLL) is the ribosomal protein RPS15. Mutated in 5.3% of CLL, it co-occurs with heterozygous TP53alterations in 36% of RPS15-mutated samples. Mutation of this mediator of ribosome maturation and translation is associated with poor disease prognosis and enriched in cohorts with del(17p) and relapsed CLL, suggesting a role in disease progression and therapeutic resistance. However, the impact of RPS15mutation on B cell function and CLL development, in the presence or absence of TP53mutation, has yet to be characterized. To this end, we developed overexpression HG3 CLL cell lines modeling four common RPS15mutations (G134R, H137Y, S138F, and S139F) and a conditional knock-in mouse model of the S138F mutation with and without heterozygous Trp53deletion (generated by crossing Rps15and Trp53mutant mice with Cd19-Cre mice).

Published
2020
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74. Expression of Sf3b1-K700Eaccelerates the Development of Chronic Lymphocytic Leukemia in a Del(13q) Murine Model

Author

Zhang, Bo, Iyer, Prajish, Jin, Meiling, Ten Hacken, Elisa, Cartun, Zachary, Hart, Kevyn, Rassenti, Laura Z., Kipps, Thomas J., Neuberg, Donna S., Carrasco, Ruben D., Wu, Catherine J., and Wang, Lili

Abstract

RNA splicing factor SF3B1is one of the most recurrently mutated genes in chronic lymphocytic leukemia (CLL), but expression of this mutation alone in murine B cells does not result in CLL. This gene mutation is often subclonal and associated with poor survival. How this mutation impacts CLL progression remains elusive. Since SF3B1mutation frequently co-occurs with chromosome 13q deletion (del(13q)), and mice with deletion of the Minimal Deleted Region (MDR) of del(13q) develop indolent CLL, we therefore asked whether co-expression of Sf3b1mutation can accelerate the onset of CLL in this murine model. If so, how does Sf3b1mutation mechanistically contribute to CLL.

Published
2020
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75. Multiplexed CRISPR In VivoEditing of CLL Loss-of-Function Lesions Models Transformation of Chronic Lymphocytic Leukemia into Richter's Syndrome

Author

Ten Hacken, Elisa, Sewastianik, Tomasz, Redd, Robert A., Fell, Geoffrey, Uduman, Mohamed, Gruber, Michaela, Yin, Shanye, Clement, Kendell, Parry, Erin Michelle, Li, Shuqiang, Hernandez-Sanchez, Maria, Billington, Leah, Witten, Elizabeth, Baranowski, Kaitlyn J, Wang, Lili, Pinello, Luca, Livak, Kenneth J., Neuberg, Donna S., Carrasco, Ruben D., and Wu, Catherine J.

Abstract

Although we have gained a wealth of knowledge from large-scale DNA sequencing studies across blood cancers, we still know little about the functional interplay of the discovered putative drivers in the generation of chronic lymphocytic leukemia (CLL) and its transformation into Richter's syndrome (RS). We have previously observed that CRISPR-Cas9 in vivoB-cell editing of common CLL loss-of-function (LOF) lesions (Atm, Trp53, Chd2, Birc3, Mga, Samhd1) can increase in vitroB cell fitness, but is not sufficient to sustain in vivoB cell survival after 12 months post-transplant.

Published
2020
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76. B Cell-Restricted Depletion of Dnmt3aActivates NotchSignaling and Causes Chronic Lymphocytic Leukemia

Author

Yin, Shanye, Biran, Anat, Kretzmer, Helene, Ten Hacken, Elisa, Parvin, Salma, Lucas, Fabienne, Uduman, Mohamed, Gutierrez, Catherine, Dangle, Nathan J, Billington, Leah, Regis, Fara, Rassenti, Laura Z., Mohammad, Arman W., Zheng, Mei, Witten, Elizabeth, Kipps, Thomas J., Aster, Jon C., Gnirke, Andreas, Neuberg, Donna S., Letai, Anthony G., Wang, Lili, Carrasco, Ruben D., Meissner, Alexander, and Wu, Catherine J.

Abstract

Previous studies have revealed a critical role of methylation deregulation in the onset and progression of chronic lymphocytic leukemia (CLL). In mammalian cells, DNA methylation is dynamically established by the DNA methyltransferase 3 (DNMT3) family of de novomethyltransferases DNMT3A. Although mutations of DNMT3Aare rarely observed in CLL, our RNA-sequencing (RNA-seq) analysis of 107 human CLLs show that low DNMT3Aexpression is associated with more aggressive disease, and supports a driving role of DNMT3Aloss in CLL. To test this hypothesis, we generated a conditional knock-out mouse model with B cell-restricted deletion of Dnmt3a. Homozygous Dnmt3adepletion in B cells resulted in the development of CD5+ B cell leukemia mimicking human CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3adepletion yielded a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haplo‐insufficient tumor suppressor.

Published
2021
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77. IKZF3Overexpression Phenocopies Gain-of-Function Mutation in Chronic Lymphocytic Leukemia

Author

Yin, Shanye, Lazarian, Gregory, Ten Hacken, Elisa, Sewastianik, Tomasz, Gohil, Satyen, Li, Shuqiang, Rassenti, Laura Z., Billington, Leah, Witten, Elizabeth, Huang, Teddy, Livak, Kenneth J., Neuberg, Donna S., Baran-Marszak, Fanny, Kipps, Thomas J., Cymbalista, Florence, Carrasco, Ruben D., and Wu, Catherine J.

Abstract

A hotspot mutation within the DNA-binding domain of IKZF3(IKZF3-L162R) has been identified as a putative driver in chronic lymphocytic leukemia (CLL); however, its functional effects are unknown. We recently confirmed its role as a CLL driver in a B cell-restricted conditional knock-in model. IKZF3mutation altered mature B cell development and signaling capacity, and induced CLL-like disease in elderly mice (~40% penetrance). Moreover, we found IKZF3-L162R acts as a gain-of-function mutation, altering DNA binding specificity and target selection of IKZF3, and resulting in overexpression of multiple B-cell receptor (BCR) genes. Consistent with the murine data, RNA-sequencing analysis showed that human CLL cells with mut-IKZF3[n=4] have an enhanced signature of BCR-signaling gene expression compared to WT-IKZF3[n=6, all IGHVunmutated] (p<0.001), and also exhibited general upregulation of key BCR-signaling regulators. These results confirm the role of IKZF3as a master regulator of BCR-signaling gene expression, with the mutation contributing to overexpression of these genes.

Published
2020
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78. B Cell Restricted Expression of Mutated IKZF3modulates BCR Signaling and Homing Pathways in a Mouse Model of CLL

Author

Lazarian, Gregory, Yin, Shanye, Ten Hacken, Elisa, Sewastianik, Tomasz, Font-tello, Alba, Joyal, Heather, Witten, Elizabeth, Zheng, Mei, Ott, Christopher J., Neuberg, Donna S, Wang, Lili, Carrasco, Ruben D., and Wu, Catherine J.

Abstract

Mutation in IKZF3(AIOLOS), a lymphoid transcription factor with a key role in B cell development and function, has been identified as a putative driver of chronic lymphocytic leukemia (CLL) through large-scale WES studies of CLL patients. Prevalent in ~3% CLLs and associated with fludarabine resistance, mutated IKZF3has been detected uniquely as a hotspot mutation (L162R), localized within the DNA binding domain. The functional effects exerted by this mutation on lymphomagenesis remain unexplored, and were the subject of the current study.

Published
2019
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79. KZF-L162RMutation Affects Splenic Mature B Cell Development and Alters Expression of Aiolos Target Genes

Author

Lazarian, Gregory, Yin, Shanye, Font-tello, Alba, Ten Hacken, Elisa, Sevastianik, Tomasz, Tom, Daniel, Regis, Fara Faye, Gill, Amy, Zheng, Mei, Georgopoulos, Katia, Neuberg, Donna S, Wang, Lili, Carrasco, Ruben D., and Wu, Catherine J.

Abstract

Large-scale DNA sequencing efforts in chronic lymphocytic leukemia (CLL) have identified a broad array of putative cancer drivers arising from somatic mutations in this disease, but functional understanding of the impact of these genetic events on CLL onset and progression remains to be elucidated. One such example is mutation in the IKZF3gene, encoding the zinc finger protein AIOLOS, mutated in ~2% of CLLs and associated with fludarabine-refractory disease. AIOLOS is a lymphoid-restricted transcription factor and a chromatin remodeler that plays an essential role in B cell development and maturation. In CLL, the IKZF3mutation, also reported in few cases of diffuse large B cell lymphoma and mantle cell lymphoma,targets a highly conserved hotspot (L162R, homologous to murine L161R) that is localized in the 2ndzinc finger of the DNA-binding domain, required for DNA sequence recognition. Given the localization of this hotspot mutation, we hypothesized that it impacts the function of AIOLOS to drive CLL.

Published
2018
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80. Integrated Genomic and Proteomic Analysis of Murine CLL-like Cells Reveals SF3B1Mutation to Impact DNA Damage Response and BCR Signaling

Author

Wang, Lili, Yin, Shanye, Martinez, Aina zurita, Regis, Fara Faye, Brooks, Angela, Herman, Sarah E.M., Ten Hacken, Elisa, Obeng, Esther, Campagna, Dean, Fleming, Mark D., Ebert, Benjamin L., Wiestner, Adrian, Leshchiner, Ignaty, Getz, Gad, Carrasco, Ruben D., and Wu, Catherine J.

Abstract

Collective large-scale sequencing efforts have unexpectedly revealed the high frequency of mutations in the splicing factor genes (SF3B1, U2AF1, SRSF2, ZRSR2) in various solid and hematological cancers, suggesting the association of splicing dysregulation with tumorigenesis. Mutations in SF3B1occur in 5-20% of patients with chronic lymphocytic leukemia (CLL) and are associated with poorer overall survival and chemotherapy resistance. These mutations are restricted to hotspots (>50% at K700E site) and strongly co-occur with ATMmutations (loss-of-function) and deletion of 11q (ATMminimal deleted region). Numerous studies including ours have demonstrated that somatic alterations in this gene cause RNA splicing dysregulation, however, how this splicing factor mutation alone and in combination with ATMdeletion impacts cellular processes and contributes to CLL remains to be fully defined.

Published
2018
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82. The Clinical BET Inhibitor, GS-5829, Is Active Against Chronic Lymphocytic Leukemia As Single Agent and in Combination with B-Cell Receptor Signaling Inhibitors

Author

Kim, Ekaterina, Ten Hacken, Elisa, Clarke, Astrid, Keating, Michael J., Wierda, William G, Ferrajoli, Alessandra, Jain, Nitin, Thompson, Philip A, Estrov, Zeev, and Burger, Jan A.

Abstract

Introduction: Despite considerable advances in the treatment of chronic lymphocytic leukemia (CLL) with targeted agents including B-cell receptor (BCR) signaling inhibitors, such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib, CLL generally remains incurable. Identifying suitable combination therapies to improve the efficacy of BCR inhibitors may induce deeper remissions and potentially permit treatment discontinuation. Inhibitors of the bromodomain and extra-terminal motif (BET) family of proteins demonstrate preclinical activity against B cell malignancies. Here, we explore the activity of a novel BET inhibitor, GS-5829, in CLL that selectively binds to acetylated lysine recognition motifs in the bromodomains of BET proteins, impeding their interaction with acetylated histones, and ultimately interfering with transcription of BET-regulated target genes.

Published
2017
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83. Immunoglobulin Heavy Chain (IgH) Knockout Inhibits Proliferation of Pre-BCR+B-Cell Acute Lymphoblastic Leukemia (B-ALL) Via a FOXO1 and MYC Dependent Mechanism

Author

Koehrer, Stefan, Havranek, Ondrej, Davis, R Eric, Seyfried, Felix, Coffey, Greg, Kim, Ekaterina, Rosin, Nathalie Y., ten Hacken, Elisa, Jäger, Ulrich, Vanura, Katrina, O’Brien, Susan, Thomas, Deborah A., Kantarjian, Hagop M., Ghosh, Dipanjan, Wang, Zhiqiang, Meyer, Lüder Hinrich, Jumaa, Hassan, and Burger, Jan A.

Abstract

A pivotal step during B-cell development is the expression of the precursor B-cell receptor (pre-BCR) by pre-B lymphocytes (cyto-Igµ+, surface-IgM-). The pre-BCR represents an immature form of the BCR and consists of two immunoglobulin heavy chains (IgH), two surrogate light chains (SLC) and the signal transducing adapter proteins Igα and Igβ. A functional pre-BCR drives proliferation of pre-B-cells, ensuring their further differentiation into mature B-cells. By immunophenotype, ~20% of B-cell acute lymphoblastic leukemia (B-ALL) cases originate from the pre-B-cell stage (pre-B-ALL) of lymphocyte development and might therefore also express the pre-BCR. In view of the importance of pre-BCR signaling for normal pre-B-cell development, we hypothesize that it is exploited by pre-B-ALL for malignant growth and proliferation.

Published
2014
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84. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

Author

Tanja Nicole Hartmann, Ayed O. Ayed, Alexandre Chigaev, Valter Gattei, Gabriele Pozzato, Antonella Zucchetto, Enrico Santinelli, Jan A. Burger, Julia Christine Gutjahr, Massimiliano Postorino, Elisabeth Bayer, Erika Tissino, Riccardo Bomben, Giovanni Del Poeta, Michele Dal Bo, Adrian Wiestner, Elisa Ten Hacken, Dania Benedetti, Pietro Bulian, Inhye E. Ahn, Larry A. Sklar, Andrea Härzschel, Alessandra Ferrajoli, Francesca Rossi, Kari G. Chaffee, Annalisa Chiarenza, Francesco Zaja, Tait D. Shanafelt, Sarah E. M. Herman, Tissino, Erika, Benedetti, Dania, Herman, Sarah E. M., ten Hacken, Elisa, Ahn, Inhye E., Chaffee, Kari G., Rossi, Francesca Maria, Bo, Michele Dal, Bulian, Pietro, Bomben, Riccardo, Bayer, Elisabeth, Härzschel, Andrea, Gutjahr, Julia Christine, Postorino, Massimiliano, Santinelli, Enrico, Ayed, Ayed, Zaja, Francesco, Chiarenza, Annalisa, Pozzato, Gabriele, Chigaev, Alexandre, Sklar, Larry A., Burger, Jan A., Ferrajoli, Alessandra, Shanafelt, Tait D., Wiestner, Adrian, Del Poeta, Giovanni, Hartmann, Tanja Nicole, Gattei, Valter, and Zucchetto, Antonella

Subjects
Lymphocytosis, Chronic lymphocytic leukemia, CLL, BTK, CD49, Kaplan-Meier Estimate, Integrin alpha4beta1, CD49d, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, immune system diseases, hemic and lymphatic diseases, Receptors, Agammaglobulinaemia Tyrosine Kinase, Immunology and Allergy, Chronic, Research Articles, Phosphoinositide-3 Kinase Inhibitors, Leukemia, biology, breakpoint cluster region, Lymphocytic, Progression-Free Survival, Antigen, 030220 oncology & carcinogenesis, Ibrutinib, medicine.symptom, Immunology, B-cell receptor, Cell Adhesion, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymph Nodes, Multivariate Analysis, Proportional Hazards Models, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Article, 03 medical and health sciences, medicine, Bruton's tyrosine kinase, business.industry, Adenine, B-Cell, Settore MED/15, medicine.disease, chemistry, biology.protein, Cancer research, business, 030215 immunology
Abstract

Tissino et al. demonstrate that in chronic lymphocytic leukemia, the VLA-4 (CD49d/CD29) integrin remains activable by B cell receptor stimulation also upon in vitro and in vivo ibrutinib exposure. Clinically, ibrutinib-treated CD49d-positive CLL patients experience reduced recirculation lymphocytosis and nodal response and inferior outcomes., The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Published
2018
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85. Calreticulin as a novel B-cell receptor antigen in chronic lymphocytic leukemia

Author

William G. Wierda, Ekaterina Kim, Kostas Stamatopoulos, Lydia Scarfò, Elisa Ten Hacken, Alessandra Ferrajoli, Jared K. Burks, Michael J. Keating, Jaap Willem Back, Paolo Ghia, Maria Gounari, Maurilio Ponzoni, Zeev Estrov, Giuseppe A. Ramirez, Jan A. Burger, Ekaterina Shimanovskaya, Ten Hacken, Elisa, Gounari, Maria, Back, Jaap Willem, Shimanovskaya, Ekaterina, Scarfò, Lydia, Kim, Ekaterina, Burks, Jared, Ponzoni, Maurilio, Ramirez, Giuseppe Alvise, Wierda, William G., Estrov, Zeev, Keating, Michael J., Ferrajoli, Alessandra, Stamatopoulos, Kosta, Ghia, Paolo, and Burger, Jan A.

Subjects
0301 basic medicine, biology, business.industry, Chronic lymphocytic leukemia, B-cell receptor, Receptors, Antigen, B-Cell, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Antigen, 030220 oncology & carcinogenesis, Immunology, biology.protein, Cancer research, Humans, Medicine, Online Only Articles, Calreticulin, business, Cells, Cultured
Published
2017
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86. Functional Differences Between IgM and IgD Signaling in Chronic Lymphocytic Leukemia

Author

Jan A. Burger, Mariela Sivina, Paolo Ghia, Susan O'Brien, Zeev Estrov, Michael J. Keating, Federico Caligaris-Cappio, William G. Wierda, Cristina Scielzo, Alessandra Ferrajoli, Ekaterina Kim, Thomas Oellerich, Elisa Ten Hacken, Ten Hacken, Elisa, Sivina, Mariela, Kim, Ekaterina, O'Brien, Susan, Wierda, William G., Ferrajoli, Alessandra, Estrov, Zeev, Keating, Michael J., Oellerich, Thoma, Scielzo, Cristina, Ghia, PAOLO PROSPERO, CALIGARIS CAPPIO, Federico, and Burger, Jan A.

Subjects
0301 basic medicine, Cell Survival, Chronic lymphocytic leukemia, Immunology, CCL3, Receptors, Antigen, B-Cell, Immunoglobulin D, Article, 03 medical and health sciences, immune system diseases, hemic and lymphatic diseases, medicine, Immunology and Allergy, Humans, Chemokine CCL4, Cells, Cultured, Adaptor Proteins, Signal Transducing, Chemokine CCL3, B-Lymphocytes, biology, Intracellular Signaling Peptides and Proteins, Blood Proteins, Protein-Tyrosine Kinases, medicine.disease, Isotype, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, 030104 developmental biology, Cellular Microenvironment, Gene Expression Regulation, Immunoglobulin M, Chemokine secretion, biology.protein, Cancer research, Proto-Oncogene Proteins c-bcl-6, Lymph Nodes, Signal transduction, Signal Transduction
Abstract

The online version of this article contains supplemental material. BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined.We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.

Published
2016

87. HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

Author

Maria Teresa Sabrina Bertilaccio, Federico Caligaris-Cappio, Manfredi Ponente, Paola Brambilla, Giovanni Tonon, Rosa Bernardi, Elisabetta Ferrero, Filippo Martinelli Boneschi, Paolo Ghia, Maurilio Ponzoni, Marina Ferrarini, Andrea Brendolan, Elisa Lenti, Elisa Ten Hacken, Lydia Scarfò, Cristina Scielzo, Daniela Belloni, Roberta Valsecchi, Nadia Coltella, Valsecchi, Roberta, Coltella, Nadia, Belloni, Daniela, Ponente, Manfredi, Ten Hacken, Elisa, Scielzo, Cristina, Scarfò, Lydia, Bertilaccio, Maria Teresa Sabrina, Brambilla, Paola, Lenti, Elisa, Boneschi, Filippo Martinelli, Brendolan, Andrea, Ferrero, Elisabetta, Ferrarini, Marina, Ghia, PAOLO PROSPERO, Tonon, Giovanni, Ponzoni, Maurilio, CALIGARIS CAPPIO, Federico, and Bernardi, Rosa

Subjects
0301 basic medicine, Stromal cell, Chronic lymphocytic leukemia, Immunology, Mice, Transgenic, Cell Communication, Biology, Biochemistry, 03 medical and health sciences, Chemokine receptor, Mice, 0302 clinical medicine, HEK293 Cell, immune system diseases, Bone Marrow, hemic and lymphatic diseases, medicine, Cell Adhesion, Tumor Microenvironment, Animals, Humans, Cell adhesion, neoplasms, Tumor microenvironment, Lymphoid Neoplasia, Cell adhesion molecule, Animal, Gene Expression Regulation, Leukemic, Stromal Cell, Hematology, Cell Biology, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Leukemia, Lymphocytic, Chronic, B-Cell, Cell biology, Mice, Inbred C57BL, Leukemia, Chemotaxis, Leukocyte, 030104 developmental biology, medicine.anatomical_structure, HEK293 Cells, 030220 oncology & carcinogenesis, Bone marrow, Stromal Cells, Spleen, Human
Abstract

Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1α is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival and propagation. Through unbiased microarray analysis, we found that in CLL cells, HIF-1α regulates the expression of important chemokine receptors and cell adhesion molecules that control the interaction of leukemic cells with bone marrow and spleen microenvironments. Inactivation of HIF-1α impairs chemotaxis and cell adhesion to stroma, reduces bone marrow and spleen colonization in xenograft and allograft CLL mouse models, and prolongs survival in mice. Of interest, we found that in CLL cells, HIF-1α is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1α messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1α target genes, including CXCR4, thus further emphasizing the relevance of HIF-1α expression to CLL pathogenesis.

Published
2016

88. Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions

Author

Federico Caligaris-Cappio, Benedetta Apollonio, E. Ten Hacken, Giorgia Simonetti, Maria Teresa Sabrina Bertilaccio, Cristina Scielzo, Paolo Ghia, Bertilaccio, Maria Teresa, Scielzo, Cristina, Simonetti, Giorgia, Ten Hacken, Elisa, Apollonio, Benedetta, Ghia, Paolo, Caligaris-Cappio, Federico, Bertilaccio, Mt, Scielzo, C, Simonetti, G, Ten Hacken, E, Apollonio, B, Ghia, PAOLO PROSPERO, and CALIGARIS CAPPIO, Federico

Subjects
Cancer Research, Xenotransplantation, medicine.medical_treatment, Chronic lymphocytic leukemia, Transplantation, Heterologous, Drug Evaluation, Preclinical, Disease, Pathogenesis, Mice, hemic and lymphatic diseases, medicine, Animals, Humans, business.industry, xenograft models, chronic lymphocytic leukemia, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Transplantation, Human tumor, Disease Models, Animal, Leukemia, Oncology, Immunology, business
Abstract

"Xenotransplantation of human tumour cells into immunodeficient mice has been a powerful pre-clinical tool in several hematologic malignancies, with the notable exception of Chronic Lymphocytic Leukemia (CLL). For several decades, this possibility was hampered by the inefficient and\/or short-term engrafment of CLL cells into available animals. The development of new generations of immunocompromised mice has allowed to partially overcome these constraints. Novel humanized animal models have been created that allow to recapitulate the pathogenesis of the disease and the complex in vivo relationships between leukemic cells and the microenvironment. In this review we discuss the development of xenograft models of CLL, how they may help elucidating the mechanisms that account for the natural history of the disease and facilitating the design of novel therapeutic approaches."

Published
2013

89. Loss-of-function lesions impact B-cell development and fitness but are insufficient to drive CLL in mouse models.

Author

ten Hacken E, Yin S, Redd R, Hernández Sánchez M, Clement K, Hoffmann GB, Regis FF, Witten E, Li S, Neuberg D, Pinello L, Livak KJ, and Wu CJ

Subjects
Mice, Animals, B-Lymphocytes pathology, Receptors, Antigen, B-Cell, Hematopoiesis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology
Published
2023
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90. Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models.

Author

Penter L, Ten Hacken E, Southard J, Lareau CA, Ludwig LS, Li S, Neuberg DS, Livak KJ, and Wu CJ

Subjects
Animals, Mice, Mitochondria genetics, Chromatin, Mutation, DNA, Mitochondrial genetics, Neoplasms genetics
Abstract

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models., Significance: mtDNA mutations can serve as natural barcodes to enable lineage tracing in murine cancer models, which can be used to provide new insights into disease biology and to identify therapeutic vulnerabilities., (©2022 American Association for Cancer Research.)

Published
2023
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91. In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.

Author

Ten Hacken E, Sewastianik T, Yin S, Hoffmann GB, Gruber M, Clement K, Penter L, Redd RA, Ruthen N, Hergalant S, Sholokhova A, Fell G, Parry EM, Broséus J, Guieze R, Lucas F, Hernández-Sánchez M, Baranowski K, Southard J, Joyal H, Billington L, Regis FFD, Witten E, Uduman M, Knisbacher BA, Li S, Lyu H, Vaisitti T, Deaglio S, Inghirami G, Feugier P, Stilgenbauer S, Tausch E, Davids MS, Getz G, Livak KJ, Bozic I, Neuberg DS, Carrasco RD, and Wu CJ

Subjects
Humans, Animals, Mice, Phosphatidylinositol 3-Kinases genetics, B-Lymphocytes, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Non-Hodgkin
Abstract

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy., Significance: Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease. This article is highlighted in the In This Issue feature, p. 101., (© 2022 American Association for Cancer Research.)

Published
2023
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92. SLAMF6 as a Regulator of Exhausted CD8 + T Cells in Cancer.

Author

Yigit B, Wang N, Ten Hacken E, Chen SS, Bhan AK, Suarez-Fueyo A, Katsuyama E, Tsokos GC, Chiorazzi N, Wu CJ, Burger JA, Herzog RW, Engel P, and Terhorst C

Subjects
Animals, Antineoplastic Agents, Immunological pharmacology, Biomarkers, Cytotoxicity, Immunologic, Disease Models, Animal, Humans, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating pathology, Melanoma, Experimental, Mice, Mice, Knockout, Neoplasms etiology, Neoplasms metabolism, Neoplasms pathology, Neoplasms therapy, Programmed Cell Death 1 Receptor metabolism, Proto-Oncogene Proteins metabolism, Signaling Lymphocytic Activation Molecule Family genetics, Tumor Microenvironment immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Immunomodulation genetics, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Signaling Lymphocytic Activation Molecule Family metabolism
Abstract

The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8 + cytotoxic T cells to an exhausted state, characterized by loss of proliferative capacity and impaired immunologic synapse formation. Efficient strategies and targets need to be identified to overcome T-cell exhaustion and further improve overall responses in the clinic. Here, we took advantage of the Eμ-TCL1 chronic lymphocytic leukemia (CLL) and B16 melanoma mouse models to assess the role of the homophilic cell-surface receptor SLAMF6 as an immune-checkpoint regulator. The transfer of SLAMF6 + Eμ-TCL1 cells into SLAMF6 -/- recipients, in contrast to wild-type (WT) recipients, significantly induced expansion of a PD-1 + subpopulation among CD3 + CD44 + CD8 + T cells, which had impaired cytotoxic functions. Conversely, administering anti-SLAMF6 significantly reduced the leukemic burden in Eμ-TCL1 recipient WT mice concomitantly with a loss of PD-1 + CD3 + CD44 + CD8 + T cells with significantly increased effector functions. Anti-SLAMF6 significantly reduced leukemic burden in the peritoneal cavity, a niche where antibody-dependent cellular cytotoxicity (ADCC) is impaired, possibly through activation of CD8 + T cells. Targeting of SLAMF6 affected tumor growth not only in B cell-related leukemia and lymphomas but also in nonhematopoietic tumors such as B16 melanoma, where SLAMF6 is not expressed. In vitro exhausted CD8 + T cells showed increased degranulation when anti-human SLAMF6 was added in culture. Taken together, anti-SLAMF6 both effectively corrected CD8 + T-cell dysfunction and had a direct effect on tumor progression. The outcomes of our studies suggest that targeting SLAMF6 is a potential therapeutic strategy., (©2019 American Association for Cancer Research.)

Published
2019
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93. Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.

Author

Ten Hacken E, Valentin R, Regis FFD, Sun J, Yin S, Werner L, Deng J, Gruber M, Wong J, Zheng M, Gill AL, Seiler M, Smith P, Thomas M, Buonamici S, Ghia EM, Kim E, Rassenti LZ, Burger JA, Kipps TJ, Meyerson ML, Bachireddy P, Wang L, Reed R, Neuberg D, Carrasco RD, Brooks AN, Letai A, Davids MS, and Wu CJ

Subjects
Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Apoptosis genetics, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Drug Screening Assays, Antitumor, Epoxy Compounds therapeutic use, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Macrolides therapeutic use, Male, Mice, Mice, Transgenic, Middle Aged, Mitochondria drug effects, Mitochondria pathology, Mutation, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Phosphoproteins genetics, Primary Cell Culture, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism, Pyrimidines pharmacology, Pyrimidines therapeutic use, RNA Splicing Factors genetics, Spliceosomes drug effects, Spliceosomes metabolism, Sulfonamides therapeutic use, Thiophenes pharmacology, Thiophenes therapeutic use, Alternative Splicing drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Epoxy Compounds pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Macrolides pharmacology, Sulfonamides pharmacology
Abstract

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.

Published
2018
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94. Calreticulin as a novel B-cell receptor antigen in chronic lymphocytic leukemia.

Author

ten Hacken E, Gounari M, Back JW, Shimanovskaya E, Scarfò L, Kim E, Burks J, Ponzoni M, Ramirez GA, Wierda WG, Estrov Z, Keating MJ, Ferrajoli A, Stamatopoulos K, Ghia P, and Burger JA

Subjects
Calreticulin analysis, Cells, Cultured, Humans, Calreticulin immunology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Receptors, Antigen, B-Cell immunology
Published
2017
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95. Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia.

Author

Fiorcari S, Maffei R, Audrito V, Martinelli S, Ten Hacken E, Zucchini P, Grisendi G, Potenza L, Luppi M, Burger JA, Deaglio S, and Marasca R

Subjects
Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Apoptosis, Biomarkers, Tumor metabolism, Cell Proliferation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Macrophages drug effects, Macrophages metabolism, Monocytes drug effects, Monocytes metabolism, Phosphorylation, Piperidines, Prognosis, Protein-Tyrosine Kinases metabolism, STAT1 Transcription Factor metabolism, STAT6 Transcription Factor metabolism, Signal Transduction drug effects, Tumor Cells, Cultured, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Macrophages immunology, Monocytes immunology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrimidines pharmacology
Abstract

In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.

Published
2016
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