MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment., This research project was supported by the national grants RTI2018-094005-B-I00 and BFU2015-66559-P from FEDER / Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación (to M.B.); PI09/00751 , PI10/02082 , and PI13/02340 from the Instituto de Salud Carlos III (to C.A.); the MECD fellowship FPU14/06542 (to D.C.); AGAUR 2019 FI_B01024 and 2022 FI_B00528 fellowships (to J.C.-R. and A.D.R.-A., respectively); and predoctoral fellowships BES-2016-077251 (to M.-M.L.P.) and PRE2019-088529 (to O.M.). Research in the M.B. lab is further supported by the following grants: the Marie Skłodowska Curie Training network “ INTERCEPT-MDS ” H2020-MSCA-ITN-2020-953407 (to M.B.); MINECO-ISCIII PIE16/00011 (to M.B.); the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to M.B.); AGAUR 2017-SGR-305 (to M.B.); and Fundació La Marató de TV3 257/C/2019 (to M.B.). C.A.’s research has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 668596 ( ChiLTERN ) and 826121 ( iPC ) as well as from CIBERehd ( CB06/04/0033 ) and AGAUR ( 2017-SGR-490 ). C.A. was supported by Ramón y Cajal ( RYC-2010-07249 ) of the Ministry of Science and Innovation of Spain. Research at the IJC is supported by the “ La Caixa” Foundation , the Fundació Internacional Josep Carreras , Celgene Spain , and the CERCA Programme / Generalitat de Catalunya.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.

Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society

The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are partic-ular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context-and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.

Mutations in genes encoding chromatin regulators are early events contributing to de-veloping asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation. In greater detail, we discuss those chromatin regulators that are frequently mutated in myelodysplastic syndromes. We discuss their role in the epigenetic regulation of normal hematopoiesis and the consequence of their mutation. Finally, we provide an update on the drugs interfering with chromatin regulation approved or in development for myelodysplastic syndromes and acute myeloid leukemia.

Motivation: Next-generation sequencing methods continue improving the annotation of genomes in part by determining the distribution of features such as epigenetic marks. Evaluating and interpreting the association between genomic regions and their features has become a common and challenging analysis in genomic and epigenomic studies. Results: With regioneR we provided an R package allowing to assess the statistical significance of pairwise associations between genomic region sets using permutation tests. We now present the R package regioneReloaded that builds upon regioneR's statistical foundation and extends the functionality for the simultaneous analysis and visualization of the associations between multiple genomic region sets. Thus, we provide a novel discovery tool for the identification of significant associations that warrant to be tested for functional interdependence.

Recurrent somatic mutations in the genes encoding the chromatin-regulatory cohesin complex and its modulators occur in a wide range of human malignancies including a high frequency in myeloid neoplasms. The cohesin complex has a ring-like structure which can enclose two strands of DNA. A first function for the complex was described in sister chromatid cohesion during metaphase avoiding defects in chromosome segregation. Later studies identified additional functions of the cohesin complex functions in DNA replication, DNA damage response, 3D genome organisation, and transcriptional regulation through chromatin looping. In this review, we will focus on STAG2 which is the most frequently mutated cohesin subunit in myeloid malignancies. STAG2 loss of function mutations are not associated with chromosomal aneuploidies or genomic instability. We hypothesize that this points to changes in gene expression as disease-promoting mechanism and summarize the current state of knowledge on affected genes and pathways. Finally, we discuss potential strategies for targeting cohesion-deficient disease cells.

Epigenetic regulation occurs on the level of compacting DNA into chromatin. The functional unit of chromatin is the nucleosome, which consists of DNA wrapped around a core of histone proteins. While canonical histone proteins are incorporated into chromatin through a replication-coupled process, structural variants of histones, commonly named histone variants, are deposited into chromatin in a replication-independent manner. Specific chaperones and chromatin remodelers mediate the locus-specific deposition of histone variants. Although histone variants comprise one of the least understood layers of epigenetic regulation, it has been proposed that they play an essential role in directly regulating gene expression in health and disease. Here, we review the emerging evidence suggesting that histone variants have a role at different stages of hematopoiesis, with a particular focus on the histone variants H2A, H3, and H1. Moreover, we discuss the current knowledge on how the dysregulation of histone variants can contribute to hematopoietic malignancies.

High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cellmigration, invasion and homotypic cell-cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial-mesenchymal plasticity.

Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society.

Evolution of vertebrate endemics in oceanic islands follows a predictable pattern, known as the island rule, according to which gigantism arises in originally small-sized species and dwarfism in large ones. Species of extinct insular giant rodents are known from all over the world. In the Canary Islands, two examples of giant rats, †Canariomys bravoi and †Canariomys tamarani, endemic to Tenerife and Gran Canaria, respectively, disappeared soon after human settlement. The highly derived morphological features of these insular endemic rodents hamper the reconstruction of their evolutionary histories. We have retrieved partial nuclear and mitochondrial data from †C. bravoi and used this information to explore its evolutionary affinities. The resulting dated phylogeny confidently places †C. bravoi within the African grass rat clade (Arvicanthis niloticus). The estimated divergence time, 650 000 years ago (95% higher posterior densities: 373 000-944 000), points toward an island colonization during the Günz-Mindel interglacial stage. †Canariomys bravoi ancestors would have reached the island via passive rafting and then underwent a yearly increase of mean body mass calculated between 0.0015 g and 0.0023 g; this corresponds to fast evolutionary rates (in darwins (d), ranging from 7.09 d to 2.78 d) that are well above those observed for non-insular mammals., For technical support, we thank the research service facilities of IJC and IGTP, the Crystallization Facility of the Max Planck Institute of Biochemistry, the ICTS NMR facility from the Scientific and Technological Centres of the University of Barcelona and Biophysics Core Facility of BMC-LMU. I.G. was a fellow of the Marie Skłodowska Curie Training network ‘ChroMe’ (H2020-MSCA-ITN-2015-675610, awarded to M.B. and A.G.L.). The project was further supported by national grants (nos. RTI2018-094005-B-I00 and BFU2015-66559-P from FEDER/Ministerio de Ciencia e Innovación—Agencia Estatal de Investigación to M.B.). Research in the participating labs was further supported by the following grants: the Marie Skłodowska Curie Training network ‘INTERCEPT-MDS’ no. H2020-MSCA-ITN-2020-953407 (to M.B.), MINECO-ISCIII no. PIE16/00011 (to M.B.); the Deutsche José Carreras Leukämie Stiftung DJCLS (no. 14R/2018 to M.B.), AGAUR (no. 2017-SGR-305 to M.B.), Fundació La Marató de TV3 (no. 257/C/2019 to M.B.), German Research Foundation Project (ID 213249687—SFB 1064 and Project ID 325871075—SFB 1309 to A.G.L.), the Spanish Ministry of Science (PID2019-110183RB-C21 to A.R.M.), Community of Madrid (P2018/BAA-4343-ALIBIRD2020-CM to A.R.M), Ramón Areces Foundation (to A.R.M.), National Science Foundation (EF-1921402 to J.M.E.L.), 2015 International Doctoral Fellowship La Caixa-Severo Ochoa (to M.F.V.), Marie Skłodowska-Curie Individual Fellowship (no. 747789 to M.M.L.), Juan de la Cierva-Incorporación (IJC2018-036657-I to M.M.L., ERC-2012-CoG-616960 to I.R.T.), MINECO (BFU2017-90114-P to I.R.T.), AGAUR (2017-SGR-324 to X.S.) and MINECO (BIO2015-70092-R and ERC-2014-CoG-648201 to X.S.). Research at the IJC is supported by the ‘La Caixa’ Foundation, Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya.

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment., This research project was supported by the national grants RTI2018-094005-B-I00 and BFU2015-66559-P from FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación (to M.B.); PI09/00751, PI10/02082, and PI13/02340 from the Instituto de Salud Carlos III (to C.A.); the MECD fellowship FPU14/06542 (to D.C.); AGAUR 2019 FI_B01024 and 2022 FI_B00528 fellowships (to J.C.-R. and A.D.R.-A., respectively); and predoctoral fellowships BES-2016-077251 (to M.-M.L.P.) and PRE2019-088529 (to O.M.). Research in the M.B. lab is further supported by the following grants: the Marie Skłodowska Curie Training network “INTERCEPT-MDS” H2020-MSCA-ITN-2020-953407 (to M.B.); MINECO-ISCIII PIE16/00011 (to M.B.); the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to M.B.); AGAUR 2017-SGR-305 (to M.B.); and Fundació La Marató de TV3 257/C/2019 (to M.B.). C.A.’s research has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 668596 (ChiLTERN) and 826121 (iPC) as well as from CIBERehd (CB06/04/0033) and AGAUR (2017-SGR-490). C.A. was supported by Ramón y Cajal (RYC-2010-07249) of the Ministry of Science and Innovation of Spain. Research at the IJC is supported by the “La Caixa” Foundation, the Fundació Internacional Josep Carreras, Celgene Spain, and the CERCA Programme/Generalitat de Catalunya.

High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell–cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial–mesenchymal plasticity., Research in the J.C. Reyes lab was funded by the Spanish Ministry of Economy and Competitiveness MCIN/AEI/10.13039/501100011033/ [PID2020-118516GB-I00]; Junta de Andalucía [P18-FR-1962 and BIO-321]; Fundación Vencer El Cancer (VEC); European Union FEDER ‘A way to build Europe’ program; research at Buschbeck lab is further supported by FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación [RTI2018-094005-B-I00]; Marie Skłodowska Curie Training network ‘INTERCEPT-MDS’ [H2020-MSCA-ITN-2020–953407]; Deutsche José Carreras Leukämie Stiftung [DJCLS 14R/2018, AGAUR 2017-SGR-305]; Fundació La Marató de TV3 257/C/2019; CABIMER is a Center partially funded by the Junta de Andalucía; E.G.-M. is the recipient of an FPI fellowship from the Spanish Ministry of Science and Innovation; L.B.-C. is the recipient of an FPU fellowship from the Spanish Ministry of Education; M.P.M. was funded by an AGAUR FI-2010 fellowship. Funding for open access charge: Spanish Ministry of Economy and Competitiveness MCIN/AEI/10.13039/501100011033/ [PID2020-118516GB-I00].

[Motivation]: Understanding the dynamics of gene expression across different cellular states is crucial for discerning the mechanisms underneath cellular differentiation. Genes that exhibit variation in mean expression as a function of Pseudotime and between branching trajectories are expected to govern cell fate decisions. We introduce scMaSigPro, a method for the identification of differential gene expression patterns along Pseudotime and branching paths simultaneously., [Results]: We assessed the performance of scMaSigPro using synthetic and public datasets. Our evaluation shows that scMaSigPro outperforms existing methods in controlling the False Positive Rate and is computationally efficient., [Availability and implementation]: scMaSigPro is available as a free R package (version 4.0 or higher) under the GPL(≥2) license on GitHub at 'github.com/BioBam/scMaSigPro' and archived with version 0.03 on Zenodo at 'zenodo.org/records/12568922'., The work is supported by the INTERCEPT-MDS Innovative Training Network, which has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 953407., Peer reviewed

Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society.

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines. Removal of macroH2A1.2 and macroH2A2 in hepatoblastoma cells affects the contact frequency of promoters and distal enhancers coinciding with changes in enhancer activity or preceding them in response to the cytokine tumor necrosis factor alpha. Although macroH2As regulate genes in both directions, they globally facilitate the nuclear factor κB (NF-κB)-mediated response. In contrast, macroH2As suppress the response to the pro-inflammatory cytokine interferon gamma. MacroH2A2 has a stronger contribution to gene repression than macroH2A1.2. Taken together, our results suggest that macroH2As have a role in regulating the response of cancer cells to inflammatory signals on the level of chromatin structure. This is likely relevant for the interaction of cancer cells with immune cells of their microenvironment., This research project was supported by the national grants RTI2018-094005-B-I00 and BFU2015-66559-P from FEDER / Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación (to M.B.); PI09/00751 , PI10/02082 , and PI13/02340 from the Instituto de Salud Carlos III (to C.A.); the MECD fellowship FPU14/06542 (to D.C.); AGAUR 2019 FI_B01024 and 2022 FI_B00528 fellowships (to J.C.-R. and A.D.R.-A., respectively); and predoctoral fellowships BES-2016-077251 (to M.-M.L.P.) and PRE2019-088529 (to O.M.). Research in the M.B. lab is further supported by the following grants: the Marie Skłodowska Curie Training network “ INTERCEPT-MDS ” H2020-MSCA-ITN-2020-953407 (to M.B.); MINECO-ISCIII PIE16/00011 (to M.B.); the Deutsche José Carreras Leukämie Stiftung DJCLS 14R/2018 (to M.B.); AGAUR 2017-SGR-305 (to M.B.); and Fundació La Marató de TV3 257/C/2019 (to M.B.). C.A.’s research has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 668596 ( ChiLTERN ) and 826121 ( iPC ) as well as from CIBERehd ( CB06/04/0033 ) and AGAUR ( 2017-SGR-490 ). C.A. was supported by Ramón y Cajal ( RYC-2010-07249 ) of the Ministry of Science and Innovation of Spain. Research at the IJC is supported by the “ La Caixa” Foundation , the Fundació Internacional Josep Carreras , Celgene Spain , and the CERCA Programme / Generalitat de Catalunya.