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Research in to the basic, epidemiological, preventive, clinical and translational aspects of leukemia and other hematologic malignancies

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Recent publications

Palau A, Mallo M, Palomo L, Rodríguez-Hernández I, Diesch J, Campos D, Granada I, Juncà J, Drexler HG, Solé F, Buschbeck M

Immunophenotypic, cytogenetic, and mutational characterization of cell lines derived from myelodysplastic syndrome patients after progression to acute myeloid leukemia.

Genes Chromosomes Cancer Mar 2017, 56 (3) 243-252. Epub 21 Nov 2016
Leukemia cell lines have been widely used in the hematology field to unravel mechanistic insights and to test new therapeutic strategies. Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases that are characterized by ineffective hematopoiesis and frequent progress to acute myeloid leukemia (AML). A few cell lines have been established from MDS patients after progression to AML but their characterization is incomplete. Here we provide a detailed description of the immunophenotypic profile of the MDS-derived cell lines SKK-1, SKM-1, F-36P; and MOLM-13. Specifically, we analyzed a comprehensive panel of markers that are currently applied in the diagnostic routine for myeloid disorders. To provide high-resolution genetic data comprising copy number alterations and losses of heterozygosity we performed whole genome single nucleotide polymorphism-based arrays and included the cell line OHN-GM that harbors the frequent chromosome arm 5q deletion. Furthermore, we assessed the mutational status of 83 disease-relevant genes. Our results provide a resource to the MDS and AML field that allows researchers to choose the best-matching cell line for their functional studies. © 2016 Wiley Periodicals, Inc.
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Etxabe A, Lara-Castillo MC, Cornet-Masana JM, Banús-Mulet A, Nomdedeu M, Torrente MA, Pratcorona M, Díaz-Beyá M, Esteve J, Risueño RM

Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem-cell functionality: A promising novel therapeutic target.

Leukemia 14 Feb 2017, . Epub 14 Feb 2017
Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous neoplasia with poor outcome, organized as a hierarchy initiated and maintained by a subpopulation with differentiation and self-renewal capacities called leukemia stem cells (LSCs). Although currently used chemotherapy is capable of initially reducing the tumor burden producing a complete remission, most patients will ultimately relapse and will succumb to their disease. As such, new therapeutic strategies are needed. AML cells differentially expressed serotonin receptors type 1 (HTR1) compared to healthy blood cells and the most primitive hematopoietic fraction; in fact, HTR1B expression on AML patient samples correlated with clinical outcome. Inhibition of HTR1s activated the apoptosis program, induced differentiation and reduced the clonogenic capacity, while minimal effect was observed on healthy blood cells. In vivo regeneration capacity of primary AML samples was disrupted upon inhibition of HTR1. The self-renewal capacity remaining in AML cells upon in vivo treatment was severely reduced as demonstrated by serial transplantation. Thus, treatment with HTR1 antagonists showed anti-leukemia effect, especially anti-LSC activity while sparing healthy blood cells. Our results highlight the importance of HTR1 in leukemogenesis and LSC survival and identify this receptor family as a new target for therapy in AML with prognostic value.Leukemia accepted article preview online, 14 February 2017. doi:10.1038/leu.2017.52.
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Buschbeck M, Hake SB

Variants of core histones and their roles in cell fate decisions, development and cancer.

Nat. Rev. Mol. Cell Biol. 1 Feb 2017, . Epub 1 Feb 2017
Histone variants endow chromatin with unique properties and show a specific genomic distribution that is regulated by specific deposition and removal machineries. These variants - in particular, H2A.Z, macroH2A and H3.3 - have important roles in early embryonic development, and they regulate the lineage commitment of stem cells, as well as the converse process of somatic cell reprogramming to pluripotency. Recent progress has also shed light on how mutations, transcriptional deregulation and changes in the deposition machineries of histone variants affect the process of tumorigenesis. These alterations promote or even drive cancer development through mechanisms that involve changes in epigenetic plasticity, genomic stability and senescence, and by activating and sustaining cancer-promoting gene expression programmes.
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Montoro J, Robledo C, Zamora L, Valcárcel D, Ramos F

Calreticulin mutations are exceedingly rare in patients with myelodysplastic syndromes with myelofibrosis.

Ann. Hematol. Feb 2017, 96 (2) 317-318. Epub 12 Oct 2016More information
Cid E, Yamamoto M, Yamamoto F

Non-AUG start codons responsible for ABO weak blood group alleles on initiation mutant backgrounds.

Sci Rep 31 Jan 2017, 7 41720. Epub 31 Jan 2017
Histo-blood group ABO gene polymorphism is crucial in transfusion medicine. We studied the activity and subcellular distribution of ABO gene-encoded A glycosyltransferases with N-terminal truncation. We hypothesized that truncated enzymes starting at internal methionines drove the synthesis of oligosaccharide A antigen in those already described alleles that lack a proper translation initiation codon. Not only we tested the functionality of the mutant transferases by expressing them and assessing their capacity to drive the appearance of A antigen on the cell surface, but we also analyzed their subcellullar localization, which has not been described before. The results highlight the importance of the transmembrane domain because proteins deprived of it are not able to localize properly and deliver substantial amounts of antigen on the cell surface. Truncated proteins with their first amino acid well within the luminal domain are not properly localized and lose their enzymatic activity. Most importantly, we demonstrated that other codons than AUG might be used to start the protein synthesis rather than internal methionines in translation-initiation mutants, explaining the molecular mechanism by which transferases lacking a classical start codon are able to synthesize A/B antigens.
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6 March 2017 12:30 - 7 March 2017 23:00
Auditorium, School of Medicine, University of Barcelona, Casanova 143

ICREA-FIJC Conference