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Josep Carreras Leukaemia Research Institute
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona
Spain
DirectionsSummary
Proper generation of B lymphocytes is fundamental for creating a humoral immune response against external and internal pathogens. B cell lymphopoiesis is a complex developmental process that implies several cellular transitions including cell commitment and early and late cellular differentiation. At each differentiation step, cells undergo extensive genetic and epigenetic reprogramming to acquire the specific gene signature characteristic of the new cellular entity generated. How specific gene expression programs are selected and maintained, resulting in the proper generation of B cells, remains a fundamental question in biology. Conversely, how the aberrant establishment of cell- and lineage-specific gene transcriptional programs leads to the development of B cell malignancies such as leukemia, lymphoma, immunodeficiencies and autoimmunity also needs extensive investigation.
Research
Our group is devoted to understanding the transcriptional and epigenetics events underlying B cell development and their potential deregulation in leukemia and lymphoma. We work on the concept that gene transcriptional repression is critical for the acquisition of proper B cell identity.
The main research lines of our laboratory are:
1. Investigating the role of the transcriptional repressor HDAC7 during B cell development
Using mouse models our laboratory has demonstrated that the histone deacetylase HDAC7 is a master transcriptional repressor during early B cell development in the bone marrow. Going beyond our current knowledge, we are currently studying its potential contribution during terminal B cell differentiation, in particular during the germinal center reaction.
2. Identifying novel epigenetic regulators essential for proper B cell generation
Based on our current knowledge we plan to define the role of additional epigenetic regulators in normal and aberrant B cell generation.
3. Establishing HDAC7 as a novel biomarker and potential therapeutic target in pro-B acute lymphoblastic leukemia (pro-B-ALL) and Diffuse Large B Cell Lymphoma (DLBCL)
We have observed that HDAC7 is under-expressed in infant and adult pro-B-ALL patients as well as in DLBCL cell lines. We aim to identify of the mechanism(s) responsible for the loss of HDAC7 expression with the main goal of uncovering novel small molecules for combinatorial and precision therapy.
4. Implementing 3D organoid cultures from DLBCL sample patients.
The implementation of 3D organoid models for testing patient responses will represent a “game-change” in the field: proof-of-concept and innovative tool to perform compound library screenings to unveil new drugs to be used in combinatorial therapy with current treatments in a personalized manner.
Collaborations
Dr Parra has several collaborative projects underway with national and international groups.
Dr Pablo Menéndez, Instituto de Investigación contra la leukemia Josep Carreras, Barcelona
Dr Thomas Graf, Centre de Regulació Genòmica (CRG), Barcelona
Dr Almudena Ramiro, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Barcelona
Dr Sergio Roa, Centro de Investigación Médica Aplicadoa, Pamplona
Dr Biola Javierre, Instituto de Investigación contra la leukemia Josep Carreras, Badalona
Dr Mireia Camós, Hospital Sant Joan de Deu, Barcelona
Dr Tokameh Mahmoudi, Erasmus Medical Center, Rotterdam
Dr Pantelis Hatzis, BSCR Alexander Fleming, Vari, Greece
Selected publications
Azagra A, Meler A, de Barrios O, Tomás-Daza L, Collazo O, Monterde B, Obiols M, Rovirosa L, Vila-Casadesús M, Cabrera-Pasadas M, Gusi-Vives M, Graf T, Varela I, Sardina JL, Javierre BM, Parra M
The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development.
Nucleic Acids Res 29 Jul 2022, . Epub 29 Jul 2022Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies.
Más informaciónde Barrios O, e Barrios O, Galaras A, Trincado JL, Azagra A, Collazo O, Meler A, Agraz-Doblas A, Bueno C, Ballerini P, Cazzaniga G, Stam RW, Varela I, De Lorenzo P, Valsecchi MG, Hatzis P, Menéndez P, Parra M.
HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia.
Leukemia, 2020 1 Dic 2020, . Not abstract available
Find out more: https://www.nature.com/articles/s41375-020-01097-x
de Barrios O, Parra M
Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia.
Int J Mol Sci 18 Mar 2021, 22 (6) . B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a highly aggressive malignancy, with poorer prognosis in infants than in adults. A genetic signature has been associated with this outcome but, remarkably, leukemogenesis is commonly triggered by genetic alterations of embryonic origin that involve the deregulation of chromatin remodelers. This review considers in depth how the alteration of epigenetic profiles (at DNA and histone levels) induces an aberrant phenotype in B lymphocyte progenitors by modulating the oncogenic drivers and tumor suppressors involved in key cancer hallmarks. DNA methylation patterns have been widely studied in BCP-ALL and their correlation with survival has been established. However, the effect of methylation on histone residues can be very different. For instance, methyltransferase
Más informaciónAzagra A, Marina-Zárate E, Ramiro AR, Javierre BM, Parra M
From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation.
Trends Immunol. 7 Dic 2019, . Epub 7 Dic 2019B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center B cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation involves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures.
Más informaciónde Barrios O, Meler A, Parra M
MYC's Fine Line Between B Cell Development and Malignancy.
Cells 24 Feb 2020, 9 (2) . Epub 24 Feb 2020The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not completely silenced until the B cell becomes fully differentiated into a plasma cell or a memory B cell. MYC has been described as a proto-oncogene that is closely involved in many cancers, including leukemia and lymphoma. Aberrant expression of MYC protein in these hematological malignancies results in an uncontrolled rate of proliferation and, thereby, a blockade of the differentiation process. MYC is not activated by mutations in the coding sequence, and, as reviewed here, its overexpression in leukemia and lymphoma is mainly caused by gene amplification, chromosomal translocations, and aberrant regulation of its transcription. This review provides a thorough overview of the role of MYC in the developmental steps of B cells, and of how it performs its essential function in an oncogenic context, highlighting the importance of appropriate MYC regulation circuitry.
Más informaciónParra M, Baptista MJ, Genescà E, Llinàs-Arias P, Esteller M
Genetics and Epigenetics of Leukemia and Lymphoma: From Knowledge to Applications, Meeting Report of the Josep Carreras Leukaemia Research Institute.
Hematol Oncol 19 Feb 2020, . Epub 19 Feb 2020The meeting, which brought together leading scientists and clinicians in the field of leukemia and lymphoma, was held at the new headquarters of the Josep Carreras Leukaemia Research Institute (IJC) in Badalona, Catalonia, Spain, September 19-20, 2019. Its purpose was to highlight the latest advances in our understanding of the molecular mechanisms driving blood cancers, and to discuss how this knowledge can be translated into an improved management of the disease. Special emphasis was placed on the role of genetic and epigenetic heterogeneity, and the exploitation of epigenetic regulation for developing biomarkers and novel treatment approaches. This article is protected by copyright. All rights reserved.
Más informaciónCurrent projects
Finding a cure for MLL-rearranged infant acute lymphoblastic leukaemia (Cure2MLL)
| Responsable: | Maribel Parra |
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| Fecha de inicio: | 01/01/2023 |
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| Fecha de finalización: | 31/12/2024 |
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Towards precision medicine in infant t(4;11) pro-B-ALL: Implementation of combinatorial therapy for targeted induction of the prognostic biomarker HDAC7
| Responsable: | Maribel Parra |
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| Código: | ISCIII-AES-2021/001927 |
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| Fecha de inicio: | 01/01/2022 |
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| Fecha de finalización: | 31/12/2024 |
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Precision medicine in infant acute lymphoblastic leukemia: Modulating specific histone deacetylases to improve prognosis
| Responsable: | Maribel Parra |
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| Fecha de inicio: | 01/10/2022 |
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| Fecha de finalización: | 30/09/2025 |
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