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1.
Cell Rep Med ; 5(2): 101421, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38340727

RESUMEN

Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19+ cells. In addition, immunocompetent mice show an intact CD80-CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.


Asunto(s)
Linfoma de Células B Grandes Difuso , Linfocitos T , Humanos , Animales , Ratones , Antígeno CTLA-4 , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/etiología , Inmunoterapia Adoptiva/métodos , Linfocitos B , Antígenos CD19/genética
2.
Eur J Haematol ; 112(6): 957-963, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38369814

RESUMEN

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.


Asunto(s)
Linfoma de Células B Grandes Difuso , Neoplasia Residual , Reacción en Cadena de la Polimerasa , Humanos , Neoplasia Residual/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Reacción en Cadena de la Polimerasa/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia , Pronóstico , ADN Tumoral Circulante/genética , Masculino , Femenino , Resistencia a Antineoplásicos/genética , Biomarcadores de Tumor , Persona de Mediana Edad , Resultado del Tratamiento
3.
Blood Adv ; 8(5): 1063-1074, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38060829

RESUMEN

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and constitutes a highly heterogenous disease. Recent comprehensive genomic profiling revealed the identity of numerous molecularly defined DLBCL subtypes, including a cluster which is characterized by recurrent aberrations in MYD88, CD79B, and BCL2, as well as various lesions promoting a block in plasma cell differentiation, including PRDM1, TBL1XR1, and SPIB. Here, we generated a series of autochthonous mouse models to mimic this DLBCL cluster and specifically focused on the impact of Cd79b mutations in this setting. We show that canonical Cd79b immunoreceptor tyrosine-based activation motif (ITAM) mutations do not accelerate Myd88- and BCL2-driven lymphomagenesis. Cd79b-mutant murine DLBCL were enriched for IgM surface expression, reminiscent of their human counterparts. Moreover, Cd79b-mutant lymphomas displayed a robust formation of cytoplasmic signaling complexes involving MYD88, CD79B, MALT1, and BTK. These complexes were disrupted upon pharmacological BTK inhibition. The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.


Asunto(s)
Adenina , Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , Piperidinas , Animales , Ratones , Adenina/análogos & derivados , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Mutación , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética
4.
Cancer Res ; 84(1): 3-5, 2024 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-37902414

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend first-line chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of approximately 65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of chimeric antigen receptor T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor-suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma. In a translational effort covering genomic and biochemical approaches, combined with in vivo validation experiments and a phase I clinical trial, they demonstrate that upon DNA damage, XPO1 selectively exports transcripts encoding proteins involved in genome maintenance via the RNA-binding proteins THOC4 and eIF4E. Pharmacologic interception of this export process enhances chemosensitivity in various lymphoma models, and combined selinexor plus chemoimmunotherapy displays a favorable toxicity profile and early evidence of efficacy in patients. See related article by Marullo et al., p. 101.


Asunto(s)
Hidrazinas , Linfoma de Células B Grandes Difuso , Humanos , Transporte Activo de Núcleo Celular , Hidrazinas/farmacología , Hidrazinas/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , ARN Mensajero
5.
Front Immunol ; 14: 1313371, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38124747

RESUMEN

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies.


Asunto(s)
Modelos Animales de Enfermedad , Linfoma de Células B Grandes Difuso , Animales , Humanos , Ratones , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico
6.
Cancer Discov ; 13(1): 216-243, 2023 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-36264161

RESUMEN

A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B cells of their competitive fitness. By identifying a phenotypically defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients. SIGNIFICANCE: Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum. See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8-11). This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Linfocitos B , Linfoma de Células B Grandes Difuso , Humanos , Animales , Ratones , Anciano , Estudios Prospectivos , Linfoma de Células B Grandes Difuso/patología , Mutación , Pronóstico
7.
Blood Cancer Discov ; 4(1): 78-97, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36346827

RESUMEN

Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell-specific Prdm1 or Spib aberrations on the background of oncogenic Myd88 and Bcl2 lesions. We deployed whole-exome sequencing, transcriptome, flow-cytometry, and mass cytometry analyses to demonstrate that Prdm1- or Spib-altered lymphomas display molecular features consistent with prememory B cells and light-zone B cells, whereas lymphomas lacking these alterations were enriched for late light-zone and plasmablast-associated gene sets. Consistent with the phenotypic evidence for increased B cell receptor signaling activity in Prdm1-altered lymphomas, we demonstrate that combined BTK/BCL2 inhibition displays therapeutic activity in mice and in five of six relapsed/refractory DLBCL patients. Moreover, Prdm1-altered lymphomas were immunogenic upon transplantation into immuno-competent hosts, displayed an actionable PD-L1 surface expression, and were sensitive to antimurine-CD19-CAR-T cell therapy, in vivo. SIGNIFICANCE: Relapsed/refractory DLBCL remains a major medical challenge, and most of these patients succumb to their disease. Here, we generated mouse models, faithfully recapitulating the biology of MYD88-driven human DLBCL. These models revealed robust preclinical activity of combined BTK/BCL2 inhibition. We confirmed activity of this regimen in pretreated non-GCB-DLBCL patients. See related commentary by Leveille et al., p. 8. This article is highlighted in the In This Issue feature, p. 1.


Asunto(s)
Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , Humanos , Ratones , Animales , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Linfocitos B , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapia , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéutico
8.
Blood ; 140(10): 1119-1131, 2022 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-35759728

RESUMEN

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B-cell lymphoma (DLBCL). However, the premalignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to 4 hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1, and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivo promoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). As with MCD, these premalignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, displayed a de novo dependence on Tlr9, and were more sensitive to inhibition of Bruton's tyrosine kinase. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all 4 genetic lesions showed a >50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCBs as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.


Asunto(s)
Linfoma de Células B Grandes Difuso , Bazo , Animales , Linfocitos B/patología , Centro Germinal/patología , Linfoma de Células B Grandes Difuso/patología , Ratones , Mutación , Bazo/patología
9.
Blood ; 139(25): 3617-3629, 2022 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-35344582

RESUMEN

Genetic alterations in the DNA damage response (DDR) pathway are a frequent mechanism of resistance to chemoimmunotherapy (CIT) in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumor cells and macrophages. Here, we show that loss of multiple different members of the DDR pathway inhibits macrophage phagocytic capacity in vitro and in vivo. Particularly, loss of TP53 led to decreased phagocytic capacity ex vivo across multiple B-cell malignancies. We demonstrate via in vivo cyclophosphamide treatment using the Eµ-TCL1 mouse model that loss of macrophage phagocytic capacity in Tp53-deleted leukemia is driven by a significant downregulation of a phagocytic transcriptomic signature using small conditional RNA sequencing. By analyzing the tumor B-cell proteome, we identified a TP53-specific upregulation of proteins associated with extracellular vesicles (EVs). We abrogated EV biogenesis in tumor B-cells via clustered regularly interspaced short palindromic repeats (CRISPR)-knockout (KO) of RAB27A and confirmed that the EVs from TP53-deleted lymphoma cells were responsible for the reduced phagocytic capacity and the in vivo CIT resistance. Furthermore, we observed that TP53 loss led to an upregulation of both PD-L1 cell surface expression and secretion of EVs by lymphoma cells. Disruption of EV bound PD-L1 by anti-PD-L1 antibodies or PD-L1 CRISPR-KO improved macrophage phagocytic capacity and in vivo therapy response. Thus, we demonstrate enhanced EV release and increased PD-L1 expression in TP53-deficient B-cell lymphomas as novel mechanisms of macrophage function alteration in CIT resistance. This study indicates the use of checkpoint inhibition in the combination treatment of B-cell malignancies with TP53 loss.


Asunto(s)
Antígeno B7-H1 , Vesículas Extracelulares , Linfoma de Células B , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Vesículas Extracelulares/metabolismo , Linfoma/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Macrófagos/metabolismo , Ratones , Neoplasias/metabolismo
10.
Blood ; 139(4): 538-553, 2022 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-34624079

RESUMEN

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/metabolismo , Glicina Hidroximetiltransferasa/antagonistas & inhibidores , Glicina Hidroximetiltransferasa/metabolismo , Animales , Linfoma de Burkitt/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , Formiatos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glicina/metabolismo , Glicina Hidroximetiltransferasa/genética , Humanos , Ratones , Terapia Molecular Dirigida , Proteolisis/efectos de los fármacos
11.
Blood ; 137(5): 646-660, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33538798

RESUMEN

Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptor Notch1/fisiología , Animales , Evolución Clonal , Progresión de la Enfermedad , Activación Enzimática , Regulación Neoplásica de la Expresión Génica , Genes p53 , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/fisiopatología , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Fosfoproteínas/fisiología , Proteínas Proto-Oncogénicas c-akt/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/fisiología , Transcriptoma , Microambiente Tumoral , Proteína p53 Supresora de Tumor/fisiología , Regulación hacia Arriba
12.
Blood Cancer Discov ; 2(1): 70-91, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33447829

RESUMEN

Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.


Asunto(s)
Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , Animales , Genes bcl-2 , Centro Germinal/metabolismo , Linfoma de Células B Grandes Difuso/genética , Ratones , Factor 88 de Diferenciación Mieloide/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética
13.
Blood ; 137(20): 2785-2799, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-33232972

RESUMEN

Aberrant B-cell receptor/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for example, in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-κB, but their differential impact on lymphoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-κB mutants. Although most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11- or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced transforming growth factor ß (TGF-ß)-mediated senescence in the lymphoma cell compartment. However, MyD88- or CARD11-mutant Eµ-myc lymphomas exhibited high-level expression of the immune-checkpoint mediator programmed cell death ligand 1 (PD-L1), thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-programmed cell death 1 checkpoint blockade, leading to direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.


Asunto(s)
Inmunidad Adaptativa , Proteínas Adaptadoras de Señalización CARD/genética , Senescencia Celular/fisiología , Guanilato Ciclasa/genética , Linfoma de Células B Grandes Difuso/inmunología , Factor 88 de Diferenciación Mieloide/genética , Proteínas de Neoplasias/genética , Linfocitos T Citotóxicos/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígenos CD79/genética , Línea Celular Tumoral , Quimiotaxis , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Genes Reporteros , Genes myc , Humanos , Inhibidores de Puntos de Control Inmunológico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense , FN-kappa B/genética , FN-kappa B/metabolismo , Mutación Puntual , Proteína 2 Ligando de Muerte Celular Programada 1/antagonistas & inhibidores , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Transcriptoma
14.
Cancers (Basel) ; 12(7)2020 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-32698538

RESUMEN

The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated disease progression in females compared to males. This difference is also reflected in an aggressive CLL mouse model with additional deletion of Tp53 besides the TCL1 transgene. Moreover, after serial adoptive transplantation of murine CLL cells, female recipients also succumbed to CLL earlier than male recipients. This sex-related disparity in the murine models is markedly contradictory to the human CLL condition. Thus, due to our observation we urge both careful consideration in the experimental design and accurate description of the Eµ-TCL1 transgenic cohorts in future studies.

15.
Leuk Lymphoma ; 61(4): 788-798, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31752573

RESUMEN

Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive lymphoma and has traditionally been subdivided into germinal center B cell-like and activated B cell-like DLBCL, using transcriptome profiling. The recent characterization of the genomic landscape of DLBCL revealed the identity of at least five molecularly-defined subclusters of DLBCL. Intriguingly, these different clusters display a different response to frontline, anthracycline-based chemo-immune therapy. Moreover, multiple, potentially actionable genomic aberrations have been identified in these clusters, including EZH2, CREBBP/EP300, and KMT2D mutations, BCL2 overexpression, PTEN inactivation, CD274 rearrangements and others. With this genomic understanding, it is possible to develop autochthonous mouse models, which capture this genomic complexity. These models can serve as pre-clinical platforms to devise molecularly targeted therapeutic intervention strategies. Here, we review the available mouse models of aggressive lymphoma and indicate which compound-mutant mice may be desirable tools to further advance the field of translational lymphoma research.


Asunto(s)
Linfoma de Células B Grandes Difuso , Animales , Linfocitos B , Modelos Animales de Enfermedad , Centro Germinal , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Ratones , Mutación
16.
Leukemia ; 34(3): 771-786, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31690822

RESUMEN

The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.


Asunto(s)
Linfoma/inmunología , Linfocitos T/inmunología , Alelos , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proliferación Celular , Etopósido/farmacología , Trasplante de Células Madre Hematopoyéticas , Linfoma/metabolismo , Ratones , Ratones Noqueados , Linfocitos T/metabolismo , Trasplante Homólogo , Resultado del Tratamiento
17.
Theranostics ; 9(21): 6047-6062, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31534536

RESUMEN

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target.


Asunto(s)
Exosomas/inmunología , Melanoma/inmunología , Chaperonas Moleculares/metabolismo , Proteínas Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Acetilación , Animales , Transformación Celular Neoplásica , Proteína p300 Asociada a E1A/metabolismo , Vesículas Extracelulares/metabolismo , Células HEK293 , Humanos , Melanoma/patología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Fragmentos de Péptidos/metabolismo , Fosfoproteínas/metabolismo , Sialoglicoproteínas/metabolismo , Microambiente Tumoral
18.
Cell Rep ; 25(4): 1027-1039.e6, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30355482

RESUMEN

Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression.


Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis , Carcinogénesis/patología , Puntos de Control del Ciclo Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Citoprotección , Daño del ADN , Resistencia a Antineoplásicos , Embrión de Mamíferos/citología , Epitelio/metabolismo , Fibroblastos/metabolismo , Dosificación de Gen , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regeneración
19.
Curr Opin Hematol ; 25(4): 315-322, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29702521

RESUMEN

PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity. RECENT FINDINGS: The results of several large lymphoma genome sequencing projects have recently been reported, including CLL, T-PLL and DLBCL. We align these discoveries with proposed mechanisms of mutation acquisition in B-cell lymphomas. Moreover, novel autochthonous mouse models of CLL have recently been generated and we discuss how these models serve as preclinical tools to drive the development of novel targeted therapeutic interventions. Lastly, we highlight the results of early clinical data on novel compounds targeting defects in the DNA damage response of CLL with a particular focus on deleterious ATM mutations. SUMMARY: Defects in DNA repair pathways are selected events in cancer, including lymphomas. Specifically, ATM deficiency is associated with PARP1- and DNA-PKcs inhibitor sensitivity in vitro and in vivo.


Asunto(s)
Transformación Celular Neoplásica , Daño del ADN , Linfoma de Células B , Mutación , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo
20.
Nat Commun ; 8(1): 153, 2017 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-28751718

RESUMEN

Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL.ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Modelos Animales de Enfermedad , Leucemia Linfocítica Crónica de Células B/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 17/genética , Ciclofosfamida/farmacología , Perfilación de la Expresión Génica/métodos , Humanos , Immunoblotting , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética
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