MYC's Fine Line Between B Cell Development and Malignancy

The 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

HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia

This paper was funded by grants to MP by the Spanish Ministry of Science, Innovation and Universities (SAF2017-87990-R and EUR2019-103835) and elaborated at the Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona) and IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona). OdB is funded by a Juan de la Cierva—Formación fellowship from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-32430). AM is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigación (AEI), through grant PRE2018-083183 (cofunded by the European Social Fund). Work in PM and CB’s lab was supported by the European Research Council (CoG-2014646903), the Spanish Ministry of Economy and Competitiveness (SAF-2016-80481-R), Uno entre Cien Mil Foundation, the Leo Messi Foundation, the Asociación Española Contra el Cáncer (AECC-CI-2015), and the ISCIII/FEDER (PI17/01028).

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development

Correct 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.FUNDING: Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2017-87990-R]; Spanish Ministry of Science and Innovation (MICINN) [EUR2019-103835]; Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona); IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona); A.M. is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigacion (AEI) [PRE2018-083183] (cofunded by the European Social Fund]; OdB. was funded by a Juan de la Cierva Formacion Fellowship from the Spanish Ministry of Science, Innovation and Universities [FJCI-2017-32430]; Postdoctoral Fellowship from the Asociacion Española Contra el Cáncer (AECC) ´ Foundation [POSTD20024DEBA]; B.M. is awardee of the Ayudas para la formacion del profesorado universitario [FPU18/00755, Ministerio de Universidades]; B.M.J. is funded by La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]; FEDER/Spanish Ministry of Science and Innovation [RTI2018-094788-A-I00]; L.T.-D. is funded by the FPI Fellowship [PRE2019- 088005]; L.R. is funded by an AGAUR FI fellowship [2019FI-B00017]; J.L.S. is funded by ISCIII [CP19/00176], co-funded by ESF, ‘Investing in your future’ and the Spanish Ministry of Science, Innovation and Universities [PID2019-111243RA-I00]. CRG acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049- S, MCIN/AEI /10.13039/501100011033). Funding for open access charge: Spanish Ministry of Science, Innovation and Universities (MICIU) [SAF2017-87990-R, EUR2019-103835].ACKNOWLEDGEMENTS: We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. We thank Dr Eric Olson (UT Southwestern Medical Center, Dallas, TX, USA) and Dr Michael Reth (Max Planck Institute of Immunology and Epigenetics, Freiburg, Germany) for kindly providing the Hdac7loxp/- and mb1- Cre mice, respectively. We thank Luc´ıa Fanlo for her assistance in technical issues and bioinformatics analysis of ChIP-seq and ATAC-seq experiments. We thank Alberto Bueno for deep analysis of our RNA-seq and hMeDIP-seq data, in order to assess the presence of differentially expressed dsRNA species. We also thank Drs Pura Munoz ˜ Canoves and Tokameh Mahmoudi for helpful comments on ´ the manuscript

The transcriptional regulator HDAC7 role in B cell development and associated malignancies

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Investigació contra la Leucèmia Fundació Josep Carreras[eng] Proper B cell identity demands a tight controlled genomic and epigenomic landscape at each stage of cellular differentiation during B lymphocyte development. It has been previously identified in our group that HDAC7 is an essential regulator of early B cell development, and its absence leads to a dramatic block at the pro-B to pre-B cell transition. In this work, we have depicted the molecular mechanisms by which HDAC7 modulates early B cell development. Specifically, HDAC7 loss induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to pro-B hematological malignancies. Actually, within this work we demonstrate that HDAC7 loss in infant acute lymphoblastic leukemia of pro- B cells (pro-B-ALL) correlates with a worse prognosis. The ectopic expression of HDAC7 in pro-B-ALL cell lines leads to a transcriptional phenotype closely related to healthy B cell progenitors, highlighting its importance in the guidance of B cell identity. However, HDAC7 role in mature B cell biology and associated malignancies is unknown. We demonstrate that HDAC7 is essential for the entry and initiation of the germinal center (GC) reaction. Upon HDAC7 loss, there is a blockade of B cell development at the pre-GC stage, which leads to the generation of aberrant GC B cells, diminished class switch recombination and plasma cell formation. We observe that HDAC7 is generally underexpressed in diffuse large B cell lymphoma (DLBCL) tumors, and its low expression is associated with a poor prognosis of the patients. HDAC7 exogenous expression in DLBCL cell lines reduces its tumorigenicity. In summary, this thesis project aims to describe first, the mechanistical regulation of HDAC7 in early B cell development, and second, HDAC7 implication in terminal B cell development. Concomitantly, we intended to decipher the potential contribution of HDAC7 deregulation in pro-B-ALL and DLBCL, which are B cell derived malignancies in the pro-B and GC B cell developmental stages, respectively.[spa] La identidad de las células B se rige por un estrecho control a nivel genético y epigenético en cada etapa de la diferenciación celular durante el desarrollo de los linfocitos B. Previamente se identificó en nuestro grupo que HDAC7 es un regulador esencial en el desarrollo temprano de células B, y su ausencia conduce a un bloqueo en la transición de las células pro-B a pre-B. En este trabajo, hemos descrito los mecanismos moleculares por los cuales HDAC7 modula el desarrollo temprano de células B. Concretamente, la pérdida de HDAC7 induce la expresión de TET2, que promueve la 5-hidroximetilación del ADN y la descompactación de la cromatina. Estos hallazgos arrojan luz sobre los mecanismos por los cuales la pérdida, o la desregulación, de HDAC7 pueden conducir a neoplasias hematológicas de células pro-B. De hecho, en este trabajo demostramos que la pérdida de HDAC7 en la leucemia linfoblástica aguda infantil de células pro-B (pro-B-ALL) se correlaciona con un peor pronóstico. La expresión ectópica de HDAC7 en líneas celulares de pro-B-ALL conduce a un fenotipo transcripcional estrechamente parecido al de células B progenitoras sanas, lo que destaca la importancia de HDAC7 en la orientación de la identidad de las células B. Sin embargo, se desconoce el papel de HDAC7 en la biología de las células B maduras y las neoplasias malignas que se le asocian. En esta tesis demostramos que HDAC7 es esencial para la entrada y el inicio de la reacción del centro germinal (CG). Tras la pérdida de HDAC7, hay un bloqueo del desarrollo de células B en la etapa previa al CG, lo que conduce a la generación de células B de CG aberrantes, a una disminución de la reacción de cambio de isotipo y a una menor producción de células plasmáticas. Observamos que HDAC7 generalmente presenta una baja expresión en pacientes con linfoma difuso de células B grandes (DLBCL), y esta baja expresión se asocia con un mal pronóstico de los pacientes. La expresión exógena de HDAC7 en líneas celulares DLBCL reduce su tumorigenicidad. En resumen, este proyecto de tesis tiene como objetivo describir, primero, la regulación mecánica de HDAC7 en el desarrollo temprano de las células B, y segundo, la implicación de HDAC7 en el desarrollo terminal de las células B. Al mismo tiempo, hemos descrito la contribución de HDAC7 en pro-B-ALL y DLBCL, que son malignidades hematológicas derivadas de células B en las etapas de desarrollo correspondientes al estadio pro-B y de CG, respectivamente

The transcriptional regulator HDAC7 role in B cell development and associated malignancies

[eng] Proper B cell identity demands a tight controlled genomic and epigenomic landscape at each stage of cellular differentiation during B lymphocyte development. It has been previously identified in our group that HDAC7 is an essential regulator of early B cell development, and its absence leads to a dramatic block at the pro-B to pre-B cell transition. In this work, we have depicted the molecular mechanisms by which HDAC7 modulates early B cell development. Specifically, HDAC7 loss induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to pro-B hematological malignancies. Actually, within this work we demonstrate that HDAC7 loss in infant acute lymphoblastic leukemia of pro- B cells (pro-B-ALL) correlates with a worse prognosis. The ectopic expression of HDAC7 in pro-B-ALL cell lines leads to a transcriptional phenotype closely related to healthy B cell progenitors, highlighting its importance in the guidance of B cell identity. However, HDAC7 role in mature B cell biology and associated malignancies is unknown. We demonstrate that HDAC7 is essential for the entry and initiation of the germinal center (GC) reaction. Upon HDAC7 loss, there is a blockade of B cell development at the pre-GC stage, which leads to the generation of aberrant GC B cells, diminished class switch recombination and plasma cell formation. We observe that HDAC7 is generally underexpressed in diffuse large B cell lymphoma (DLBCL) tumors, and its low expression is associated with a poor prognosis of the patients. HDAC7 exogenous expression in DLBCL cell lines reduces its tumorigenicity. In summary, this thesis project aims to describe first, the mechanistical regulation of HDAC7 in early B cell development, and second, HDAC7 implication in terminal B cell development. Concomitantly, we intended to decipher the potential contribution of HDAC7 deregulation in pro-B-ALL and DLBCL, which are B cell derived malignancies in the pro-B and GC B cell developmental stages, respectively.[spa] La identidad de las células B se rige por un estrecho control a nivel genético y epigenético en cada etapa de la diferenciación celular durante el desarrollo de los linfocitos B. Previamente se identificó en nuestro grupo que HDAC7 es un regulador esencial en el desarrollo temprano de células B, y su ausencia conduce a un bloqueo en la transición de las células pro-B a pre-B. En este trabajo, hemos descrito los mecanismos moleculares por los cuales HDAC7 modula el desarrollo temprano de células B. Concretamente, la pérdida de HDAC7 induce la expresión de TET2, que promueve la 5-hidroximetilación del ADN y la descompactación de la cromatina. Estos hallazgos arrojan luz sobre los mecanismos por los cuales la pérdida, o la desregulación, de HDAC7 pueden conducir a neoplasias hematológicas de células pro-B. De hecho, en este trabajo demostramos que la pérdida de HDAC7 en la leucemia linfoblástica aguda infantil de células pro-B (pro-B-ALL) se correlaciona con un peor pronóstico. La expresión ectópica de HDAC7 en líneas celulares de pro-B-ALL conduce a un fenotipo transcripcional estrechamente parecido al de células B progenitoras sanas, lo que destaca la importancia de HDAC7 en la orientación de la identidad de las células B. Sin embargo, se desconoce el papel de HDAC7 en la biología de las células B maduras y las neoplasias malignas que se le asocian. En esta tesis demostramos que HDAC7 es esencial para la entrada y el inicio de la reacción del centro germinal (CG). Tras la pérdida de HDAC7, hay un bloqueo del desarrollo de células B en la etapa previa al CG, lo que conduce a la generación de células B de CG aberrantes, a una disminución de la reacción de cambio de isotipo y a una menor producción de células plasmáticas. Observamos que HDAC7 generalmente presenta una baja expresión en pacientes con linfoma difuso de células B grandes (DLBCL), y esta baja expresión se asocia con un mal pronóstico de los pacientes. La expresión exógena de HDAC7 en líneas celulares DLBCL reduce su tumorigenicidad. En resumen, este proyecto de tesis tiene como objetivo describir, primero, la regulación mecánica de HDAC7 en el desarrollo temprano de las células B, y segundo, la implicación de HDAC7 en el desarrollo terminal de las células B. Al mismo tiempo, hemos descrito la contribución de HDAC7 en pro-B-ALL y DLBCL, que son malignidades hematológicas derivadas de células B en las etapas de desarrollo correspondientes al estadio pro-B y de CG, respectivamente

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development

Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2017-87990-R]; Spanish Ministry of Science and Innovation (MICINN) [EUR2019-103835]; Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona); IDIBELL Research Institute (L'Hospitalet de Llobregat, Barcelona); A.M. is funded by the SpanishMinistry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigación (AEI) [PRE2018- 083183] (cofunded by the European Social Fund]; OdB. was funded by a Juan de la Cierva Formación Fellowship from the Spanish Ministry of Science, Innovation and Universities [FJCI-2017-32430]; Postdoctoral Fellowship from the Asociación Española Contra el Cáncer (AECC) Foundation [POSTD20024DEBA]; B.M. is awardee of the Ayudas para la formación del profesorado universitario [FPU18/00755, Ministerio de Universidades]; B.M.J. is funded by La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]; FEDER/SpanishMinistry of Science and Innovation [RTI2018-094788-A-I00]; L.T.-D. is funded by the FPI Fellowship [PRE2019- 088005]; L.R. is funded by an AGAUR FI fellowship [2019FI-B00017]; J.L.S. is funded by ISCIII [CP19/00176], co-funded by ESF, 'Investing in your future' and the Spanish Ministry of Science, Innovation and Universities [PID2019-111243RA-I00]. CRG acknowledge the support of the SpanishMinistry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049- S, MCIN/AEI /10.13039/501100011033). Funding for open access charge: Spanish Ministry of Science, Innovation and Universities (MICIU) [SAF2017-87990-R, EUR2019-103835].Correct 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