Mechanisms of epigenetic inheritance of variable traits through the germline.
ReproductionJun 2020, 159(6)R251-R263. Epub 22 Abr 2020
During the past half century, evidence for inheritance of variable traits has accumulated from experiments in plants and animals and epidemiological studies in humans. Here, we summarize some of the reported cases of epigenetic inheritance and the proposed mechanisms involved in the transmission of non-genetic information between generations in plants, nematodes, flies and mammals. It has long been accepted that information is epigenetically inherited in plants. Although many questions regarding the underlying mechanisms remain to be answered, it is now evident that epigenetic mechanisms are also responsible for the transmission of phenotypes in animals. We highlight similarities and differences between models and species.
Hajek R, Pour L, Ozcan M, Martin Sánchez J, García Sanz R, Anagnostopoulos A, Oriol A, Cascavilla N, Terjung A, Lee Y, Briso EM, Dobkowska E, Hauns B, Špička I
A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Eur. J. Haematol.May 2020, 104(5)435-442. Epub 7 Mar 2020
We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies.
Molina O, Vinyoles M, Granada I, Roca-Ho H, Gutierrez-Agüera F, Valledor L, López-López CM, Rodríguez-González P, Trincado JL, Tirados-Menéndez S, Pal D, Ballerini P, Den Boer ML, Plensa I, Perez-Iribarne MDM, Rodriguez-Perales S, Calasanz MJ, Ramírez M, Rodríguez R, Camos M, Calvo M, Bueno C, Menendez P
Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL.
Blood22 Abr 2020, . Epub 22 Abr 2020
B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, and high-hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD is an initiating oncogenic event affiliated to childhood B-ALL, the mitotic and chromosomal defects associated to HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated to chromosome alignment defects at the metaphase plate leading to robust chromosome segregation defects and non-modal karyotypes. Mechanistically, biochemical, functional and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness and mis-localization of the chromosome passenger complex proteins Aurora B Kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and impaired spindle assembly checkpoint (SAC) thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated to defective condensin complex, AURKB and SAC.
Godfrey L, Crump NT, O'Byrne S, Lau IJ, Rice S, Harman JR, Jackson T, Elliott N, Buck G, Connor C, Thorne R, Knapp DJHF, Heidenreich O, Vyas P, Menendez P, Inglott S, Ancliff P, Geng H, Roberts I, Roy A, Milne TA
H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells.
Leukemia2 Abr 2020, . Epub 2 Abr 2020
MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
Vidal-Crespo A, Matas-Céspedes A, Rodriguez V, Rossi C, Valero JG, Serrat N, Sanjuan-Pla A, Menéndez P, Roué G, López-Guillermo A, Giné E, Campo E, Colomer D, Bezombes C, van Bueren JL, Chiu C, Doshi P, Pérez-Galán P
Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens.
CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical
O'Byrne S, Elliott N, Rice S, Buck G, Fordham N, Garnett C, Godfrey L, Crump NT, Wright G, Inglott S, Hua P, Psaila B, Povinelli B, Knapp DJHF, Agraz-Doblas A, Bueno C, Varela I, Bennett P, Koohy H, Watt SM, Karadimitris A, Mead AJ, Ancliff P, Vyas P, Menendez P, Milne TA, Roberts I, Roy A
Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs.
Blood26 Sep 2019, 134(13)1059-1071. Epub 5 Ago 2019
Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19
Recasens-Zorzo C, Cardesa-Salzmann T, Petazzi P, Ros-Blanco L, Esteve-Arenys A, Clot G, Guerrero-Hernández M, Rodríguez V, Soldini D, Valera A, Moros A, Climent F, González-Barca E, Mercadal S, Arenillas L, Calvo X, Mate JL, Gutiérrez-García G, Casanova I, Mangues R, Sanjuan-Pla A, Bueno C, Menéndez P, Martínez A, Colomer D, Tejedor RE, Teixidó J, Campo E, López-Guillermo A, Borrell JI, Colomo L, Pérez-Galán P, Roué G
Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.
HaematologicaAbr 2019, 104(4)778-788. Epub 28 Jun 2018
Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells
Fernandez AF, Bayón GF, Sierra MI, Urdinguio RG, Toraño EG, García M, Carella A, Lopez V, Santamarina P, Pérez RF, Belmonte T, Ramon Tejedor J, Cobo I, Menendez P, Mangas C, Ferrero C, Rodrigo L, Astudillo A, Ortea I, Cueto Díaz S, Rodríguez-Gonzalez P, Ignacio García Alonso J, Mollejo M, Meléndez B, Dominguez G, Bonilla F, Fraga MF
Loss of 5hmC identifies a new type of aberrant DNA hypermethylation in glioma.
Hum. Mol. Genet.5 Jun 2018, . Epub 5 Jun 2018
Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5mC in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island (CGI) shores. The DNA regions containing these CpG sites were enriched in H3K4me2 and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. As this 5mC gain is inversely correlated with loss of 5hmC and has not been identified with classical sodium bisulfite-based technologies, we conclude that our data identifies a novel 5hmC-dependent type of aberrant DNA hypermethylation in glioma.