Jose A Martinez-Climent

Universidad de Navarra, Iruña, Navarre, Spain

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Publications (73)532.49 Total impact

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    ABSTRACT: Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 gene are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted, therefore identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here, we integrated genome-wide DNA promoter methylation profiling with gene expression profiling, and clinical and biologic variables. An unsupervised clustering analysis of a test series of 98 samples identified two clusters with different degrees of promoter methylation. The cluster comprising samples with higher promoter methylation (High-M) had a poorer overall survival compared to the Low-M cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several pro-survival lymphoma genes were un-methylated and over-expressed. A model based on the methylation of three genes (CACNB2, HTRA1 and KLF4) identified a poorer outcome patient subset. Exposure of SMZL cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(12). DOI:10.1182/blood-2014-08-596247 · 10.43 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2693-2693. DOI:10.1158/1538-7445.AM2014-2693 · 9.28 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by 'hit-and-run' oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a 'hit-and-run' role in lymphomagenesis.
    Nature Communications 06/2014; 5:3904. DOI:10.1038/ncomms4904 · 10.74 Impact Factor
  • Jose A Martinez-Climent
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    ABSTRACT: Extranodal mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinical-pathological entity that can be distinguished from other lymphomas by a number of unique features, including their location in various extranodal sites, being preceded by chronic inflammatory or infection processes; a characteristic histopathological picture; and the presence of exclusive chromosomal translocations which increase MALT1 proteolytic activity to promote constitutive NF-κB signaling and eventually drive lymphomagenesis.
    Current Opinion in Hematology 05/2014; DOI:10.1097/MOH.0000000000000051 · 4.05 Impact Factor
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    ABSTRACT: Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, two missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of pro-apoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results may anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance.
    Blood 04/2014; 123(26). DOI:10.1182/blood-2014-03-560284 · 10.43 Impact Factor
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    ABSTRACT: In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.
    Cell cycle (Georgetown, Tex.) 03/2014; 13(11). DOI:10.4161/cc.28629 · 5.01 Impact Factor
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    ABSTRACT: We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF-related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6-driven lymphomas may contribute to lymphomagenesis.
    British Journal of Haematology 06/2013; 162(5). DOI:10.1111/bjh.12440 · 4.96 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) is associated with infiltration of peritumoral parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the peritumoral (PT) area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in 2D and 3D migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation is required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators αVβ3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, β3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVβ3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighbouring tissue.
    Stem Cells 06/2013; 31(6). DOI:10.1002/stem.1349 · 7.70 Impact Factor
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    ABSTRACT: B cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other key transcriptional regulators. FOXP1 is a transcription factor that regulates early B cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B cell subpopulations revealed that FOXP1 shows opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. ChIP-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes typically involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of GCs in the spleen, showing a modest increase in naïve and marginal-zone B cells, and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired the transcription of non-coding γ1 germline transcripts (GLTs) and inhibited efficient class-switching to the IgG1 isotype. These studies show that FOXP1 is physiologically down-regulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B cell activation, potentially contributing to B cell lymphomagenesis.
    Blood 04/2013; 121(21). DOI:10.1182/blood-2012-10-462846 · 10.43 Impact Factor
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    ABSTRACT: Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a lymphoblastic leukemia B cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced by C/EBPα to transdifferentiate into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy for treating B cell malignancies.
    Cell Reports 03/2013; DOI:10.1016/j.celrep.2013.03.003 · 7.21 Impact Factor
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    ABSTRACT: The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation.
    Nature Communications 01/2013; 4:1338. DOI:10.1038/ncomms2334 · 10.74 Impact Factor
  • Melissa Rieger Menanteau, Jose A Martinez-Climent
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    ABSTRACT: Genomic profiling of mantle cell lymphoma (MCL) cells has enabled a better understanding of the complex mechanisms underlying the pathogenesis of disease. Besides the t(11;14)(q13;q32) leading to cyclin D1 overexpression, MCL exhibits a characteristic pattern of DNA copy number aberrations that differs from those detected in other B-cell lymphomas. These genomic changes disrupt selected oncogenes and suppressor genes that are required for lymphoma development and progression, many of which are components of cell cycle, DNA damage response and repair, apoptosis, and cell-signaling pathways. Additionally, some of them may represent effective therapeutic targets. A number of genomic and molecular abnormalities have been correlated with the clinical outcome of patients with MCL and are considered prognostic factors. However, only a few genomic markers have been shown to predict the response to current or novel targeted therapies. One representative example is the high-level amplification of the BCL2 gene, which predicts a good response to pro-apoptotic BH3 mimetic drugs. In summary, genomic analyses have contributed to the substantial advances made in the comprehension of the pathogenesis of MCL, providing a solid basis for the identification of optimal therapeutic targets and for the design of new molecular therapies aiming to cure this fatal disease.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 973:147-63. DOI:10.1007/978-1-62703-281-0_9 · 1.29 Impact Factor
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    ABSTRACT: MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.
    Cancer cell 12/2012; 22(6):812-24. DOI:10.1016/j.ccr.2012.11.003 · 23.89 Impact Factor
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    ABSTRACT: Comment on: Vicente-Dueñas C, et al. Proc Natl Acad Sci USA 2012; 109:10534-9.
    Cell cycle (Georgetown, Tex.) 08/2012; 11(16):2961-2. DOI:10.4161/cc.21264 · 5.01 Impact Factor
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    ABSTRACT: Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B-cell lymphomas (P < 0·00001). The presence of unmutated IGHV, genomic complexity, 17p13-TP53 deletion and 8q-MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studies narrowed down a commonly deleted region of 2·7 Mb in 7q32.1-q32.2 spanning a region between the SND1 and COPG2 genes. High-throughput sequencing analysis of the 7q32-deleted segment did not identify biallelic deletions/insertions or clear pathogenic gene mutations, but detected six nucleotide changes in IRF5 (n = 2), TMEM209 (n = 2), CALU (n = 1) and ZC3HC1 (n = 1) not found in healthy individuals. Comparative expression analysis found a fourfold down-regulation of IRF5 gene in lymphomas with 7q32 deletion versus non-deleted tumours (P = 0·032). Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased proliferation and increased apoptosis in vitro, and impaired lymphoma development in vivo. These results show that cryptic deletions, insertions and/or point mutations inactivating genes within 7q32 are not common in SMZL, and suggest that IRF5 may be a haploinsufficient tumour suppressor in this lymphoma entity.
    British Journal of Haematology 07/2012; 158(6):712-26. DOI:10.1111/j.1365-2141.2012.09226.x · 4.96 Impact Factor
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    ABSTRACT: Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.
    Proceedings of the National Academy of Sciences 06/2012; 109(26):10534-9. DOI:10.1073/pnas.1204127109 · 9.81 Impact Factor
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    ABSTRACT: LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis.
    Blood 04/2012; 119(23):5478-91. DOI:10.1182/blood-2012-01-403154 · 10.43 Impact Factor
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    ABSTRACT: Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1517-26. DOI:10.1038/leu.2012.31 · 9.38 Impact Factor
  • X Agirre, J Á Martínez-Climent, M D Odero, F Prósper
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNA molecules that can negatively regulate gene expression at the post-transcriptional level. miRNA expression patterns are regulated during development and differentiation of the hematopoietic system and have an important role in cell processes such as proliferation, apoptosis, differentiation or even in tumorigenesis of human tumors and in particular of hematological malignancies such as acute leukemias. Various miRNAs and their functions have been intensively studied in acute leukemias but the mechanisms that control their expression are largely unknown for the majority of aberrantly expressed miRNAs. miRNA expression can be regulated by the same genetic mechanism that modulate protein coding genes such as mutation, deletion, amplification, loss of heterozygosity and translocations. In this review we focus on the regulation of miRNAs in acute leukemias mediated by alterations in epigenetic mechanisms such as DNA methylation and histone code, describing the role of these alterations in the pathogenesis, diagnosis and prognosis of acute leukemias and their possible use as new therapeutic targets and biomarkers.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2011; 26(3):395-403. DOI:10.1038/leu.2011.344 · 9.38 Impact Factor
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    ABSTRACT: PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
    Blood 09/2011; 118(20):5517-27. DOI:10.1182/blood-2011-03-344374 · 10.43 Impact Factor

Publication Stats

2k Citations
532.49 Total Impact Points


  • 2005–2015
    • Universidad de Navarra
      • Department of Oncology
      Iruña, Navarre, Spain
  • 2004–2011
    • Centro Nacional de Investigaciones Oncológicas
      • Molecular Pathology Programme
      Madrid, Madrid, Spain
  • 2009
    • University of California, San Francisco
      San Francisco, California, United States
  • 2005–2007
    • University of Leicester
      Leiscester, England, United Kingdom
  • 1998–2004
    • University of Valencia
      Valenza, Valencia, Spain
  • 2003
    • Hospital Francesc De Borja De Gandia
      Gandía, Valencia, Spain
    • Hospital General Universitario Gregorio Marañón
      Madrid, Madrid, Spain
  • 1995–1996
    • University of Chicago
      • • Section of Hematology/Oncology
      • • Department of Medicine
      Chicago, IL, United States
    • The University of Chicago Medical Center
      • Department of Medicine
      Chicago, IL, United States