Revistas
Revista:
CELLS
ISSN:
2073-4409
Año:
2023
Vol.:
12
N°:
1
Págs.:
186
There is growing evidence that Ph-negative myeloproliferative neoplasms (MPNs) are disorders in which multiple molecular mechanisms are significantly disturbed. Since their discovery, CALR driver mutations have been demonstrated to trigger pathogenic mechanisms apart from the well-documented activation of JAK2/MPL-related pathways, but the lack of experimental models harboring CALR mutations in a JAK2/MPL knockout background has hindered the research on these non-canonical mechanisms. In this study, CRISPR/Cas9 was performed to introduce homozygous patient-like calreticulin mutations in a C. elegans model that naturally lacks JAK2 and MPL orthologs. Whole-genome transcriptomic analysis of these worms was conducted, and some of the genes identified to be associated with processes involved in the pathogenesis of MPNs were further validated by qPCR. Some of the transcriptomic alterations corresponded to typically altered genes and processes in cancer and Ph-negative MPN patients that are known to be triggered by mutant calreticulin without the intervention of JAK2/MPL. However, interestingly, we have also found altered other processes described in these diseases that had not been directly attributed to calreticulin mutations without the intervention of JAK2 or MPL. Thus, these results point to a new experimental model for the study of the JAK2/MPL-independent mechanisms of mutant calreticulin that induce these biological alterations, which could be useful to study unknown non-canonical effects of the mutant protein. The comparison with a calreticulin null strain revealed that the alteration of all of these processes seems to be a consequence of a loss of function of mutant calreticulin in the worm, except for the dysregulation of Hedgehog signaling and flh-3. Further analysis of this model could help to delineate these mechanisms, and the verification of these results in mammalian models may unravel new potential therapeutic targets in MPNs. As far as we know, this is the first time that a C. elegans strain with patient-like mutations is proposed as a potential model for leukemia research.
Revista:
JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN:
2051-1426
Año:
2023
Vol.:
11
N°:
2
Págs.:
e006113
BackgroundApproximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.MethodsHere, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.ResultsVenetoclax treatment demonstrated specific killing of MYC+/BCL2(+) lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.ConclusionsThese results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.
Revista:
SCIENTIA ET FIDES
ISSN:
2300-7648
Año:
2020
Vol.:
8
N°:
2
Págs.:
323 - 349
In this article, I analyse the texts in which Joseph Ratzinger deals with biological evolution, particularly in the context of the compatibility between faith in creation and acceptance of the theory of evolution. His first writings on the topic, until 1979, contain the most elaborate and deepest theological and philosophical insights, with a defence of the compatibility between faith in creation and the theory of evolution when the boundaries of their respective explanatory frameworks are respected. At the beginning of the 1980s, still at the philosophical level, Ratzinger engages with the work some atheist scientists who try to portray evolution as a "first philosophy". The 1999 lecture at the Sorbonne University marks the beginning of a period in which he criticizes some technical aspects of the theory of evolution, a position that seems to have been prompted by contacts with anti-evolution German intellectuals in the previous years. After the 2006 meeting of the Schulerkreis in Castel Gandolfo, in which his criticism of evolution reaches its climax, his references to the topic were few and he returned to the philosophical ideas expressed in his earlier writings, stressing that the intrinsic rationality and inner logic of the cosmos point to a creating Reason.
Revista:
MOLECULAR AND CLINICAL ONCOLOGY
ISSN:
2049-9450
Año:
2019
Vol.:
10
N°:
6
Págs.:
639 - 643
In recent years it has been shown that the causes of chronic myeloproliferative neoplasms (MPNs) are more complex than a simple signaling aberration and many other mutated genes affecting different cell processes have been described. For instance, mutations in genes encoding epigenetic regulators are more frequent than expected. One of the latest genes described as mutated is SET binding protein 1 (SETBP1). In silico tools have revealed that there are several human SETBP1 paralogous to nuclear receptor binding SET domain protein 1 (NSD1), NSD2 and NSD3, for example, which are also involved in the development of other hematological malignancies. Therefore, the present study analyzed the mutational status of NSD1, NSD2, NSD3 and SETBP1 in BCR-ABL1 negative MPNs with or without Janus kinase 2 (JAK2) p.V617F mutation. The present study revealed that the NSD genes are not frequently mutated in MPNs. However, a novel SETBP1 mutation was identified in a patient with p.V617F JAK2 positive primary myelofibrosis. These results provide further insight into the genetic complexity of MPNs.
Revista:
HAEMATOLOGICA
ISSN:
0390-6078
Año:
2017
Vol.:
102
N°:
8
Págs.:
e328 - e331
Revista:
SCIENTIA ET FIDES
ISSN:
2300-7648
Año:
2016
Vol.:
4
N°:
2
Págs.:
97 - 114
I review Mariano Artigas' appraisal of Evolution as reflected in some of his works. I find that his perception of evolutionary theory changed from a critical attitude, mainly directed against the modern synthesis of the twentieth century, to a more lenient approach as he incorporated new elements into his reflections. However, he did not fully appreciate some of the advances made in evolutionary biology in recent years. I provide some examples, taken from the field of evolutionary genomics, which shed new light on why evolvability is a necessary property of living beings and how adaptation proceeds through the rewiring of modular gene regulatory networks, resulting in a remarkable degree of phenotypic plasticity. This view provides a richer understanding of two key elements of Artigas' portrayal of the modern worldview: dynamism and patterning.
Revista:
BIOTECHNIQUES
ISSN:
0736-6205
Año:
2014
Vol.:
56
N°:
6
Págs.:
327 - 329
When studying mutations in DNA samples, determining whether novel sequence changes are somatic mutations or germline polymorphisms can be difficult. Here we describe a novel and very simple approach for identification of somatic mutations and loss of heterozygosity (LoH) events in DNA samples where no matched tissue sample is available. Our method makes use of heterozygous polymorphisms that are located near the putative mutation to trace both germinal alleles.
Autores:
Eder Azanza, L.; Navarro Herrera, D.; Aranaz, Paula; et al.
Revista:
LEUKEMIA
ISSN:
0887-6924
Año:
2014
Vol.:
28
N°:
10
Págs.:
2106 - 2109
Revista:
LEUKEMIA AND LYMPHOMA
ISSN:
1042-8194
Año:
2013
Vol.:
54
N°:
2
Págs.:
428 - 431
Revista:
BIOINFORMATICS
ISSN:
1367-4803
Año:
2013
Vol.:
29
N°:
20
Págs.:
2539 - 2546
Motivation: Gene fusions resulting from chromosomal aberrations are an important cause of cancer. The complexity of genomic changes in certain cancer types has hampered the identification of gene fusions by molecular cytogenetic methods, especially in carcinomas. This is changing with the advent of next-generation sequencing, which is detecting a substantial number of new fusion transcripts in individual cancer genomes. However, this poses the challenge of identifying those fusions with greater oncogenic potential amid a background of 'passenger' fusion sequences.
Results: In the present work, we have used some recently identified genomic hallmarks of oncogenic fusion genes to develop a pipeline for the classification of fusion sequences, namely, Oncofuse. The pipeline predicts the oncogenic potential of novel fusion genes, calculating the probability that a fusion sequence behaves as 'driver' of the oncogenic process based on features present in known oncogenic fusions. Cross-validation and extensive validation tests on independent datasets suggest a robust behavior with good precision and recall rates. We believe that Oncofuse could become a useful tool to guide experimental validation studies of novel fusion sequences found during next-generation sequencing analysis of cancer transcriptomes.
Revista:
Haematologica-journal of Hematology
ISSN:
1138-0381
Año:
2012
Vol.:
97
N°:
8
Págs.:
1234 -1241
Revista:
PLOS COMPUTATIONAL BIOLOGY
ISSN:
1553-7358
Año:
2012
Vol.:
8
N°:
12
Págs.:
e1002797
Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5' TPGs and to more stable 3'-UTR regions of 3' TPGs. Furthermore, expression profiling of 5' TPGs and of interaction partners of 3' TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5' and 3' TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5' and 3' TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.
Revista:
Leukemia & Lymphoma
ISSN:
1042-8194
Año:
2011
Vol.:
53
N°:
6
Págs.:
1230-1233
Revista:
Genes chromosomes & cancer (Print)
ISSN:
1045-2257
Año:
2011
Vol.:
2
N°:
5
Págs.:
593 - 596
Revista:
Leukemia Research
ISSN:
0145-2126
Año:
2011
Vol.:
35
N°:
11
Págs.:
1537 - 1539
Revista:
CANCER GENETICS AND CYTOGENETICS
ISSN:
0165-4608
Año:
2010
Vol.:
199
N°:
1
Págs.:
1 - 8
BCR/ABL1-negative chronic myeloproliferative neoplasms (CMPNs) are a heterogeneous group of clonal hematological malignancies. Over recent years, some genetic events in tyrosine lcinase (TK) genes have been described as causal events of these diseases. To identify new genetic aberrations underlying these diseases, we used denaturing high performance liquid chromatography and fluorescence in situ hybridization (FISH) to analyze 17 genes from two receptor-TK families (III and IV) and from three cytoplasmic-TK families (Syk, Abl, and Jak) on samples from 44 BCR/ABL1-negative and JAK2(V617F)-negative CMPN patients with different clinical phenotypes. Although screening by FISH did not reveal novel chromosomal aberrations, several sequence changes were detected. None of them were frequent events, but we identified a new potential activating mutation in the FERM domain of JAK2(R340Q). None of the germline JAK2(V617F) singlenucleotide polymorphisms detected differed in distribution between patients and control subjects. In summary, data presented here show that these genes are not frequently mutated or rearranged in CMPNs, suggesting that molecular events causing these disorders must be located in other genes.
Revista:
LEUKEMIA AND LYMPHOMA
ISSN:
1042-8194
Año:
2010
Vol.:
51
N°:
9
Págs.:
1720 - 1726
Hematological malignancies with eosinophilia are often associated with fusions in PDGFRA, PDGFRB, or FGFR1 genes. RT-PCR has proved to be useful for finding new PDGFRA gene fusions, but some studies have shown overexpression of the TK domain which cannot be explained by the existence of such aberrations. This fact could be related to the expression of alternative PDGFRA transcripts. We show that quantification of the expression of three different PDGFRA fragments discriminates between PDGFRA alternative transcripts and fusion genes, and we have tested this novel methodological approach in a group of eosinophilia cases. Our data show that alternative PDGFRA transcripts should be taken into account when screening for PDGFRA aberrations, such as gene fusions, by RT-PCR. Expression from an internal PDGFRA promoter seems to be a frequent event, in both normal and leukemic samples, and is probably related to physiological conditions, but it could have a role in other tumors. Even so, we show that our RQ-PCR methodology can discriminate expression of alternative transcripts from the presence of X-PDGFRA fusion genes.
Revista:
BLOOD
ISSN:
0006-4971
Año:
2010
Vol.:
115
N°:
3
Págs.:
615 - 625
Acute myeloid leukemias (AMLs) result from multiple genetic alterations in hematopoietic stem cells. We describe a novel t(12; 18)(p13;q12) involving ETV6 in a patient with AML. The translocation resulted in overexpression of SETBP1 (18q12), located close to the breakpoint. Overexpression of SETBP1 through retroviral insertion has been reported to confer growth advantage in hematopoietic progenitor cells. We show that SETBP1 overexpression protects SET from protease cleavage, increasing the amount of full-length SET protein and leading to the formation of a SETBP1 SET-PP2A complex that results in PP2A inhibition, promoting proliferation of the leukemic cells. The prevalence of SETBP1 overexpression in AML at diagnosis (n=192) was 27.6% and was associated with unfavorable cytogenetic prognostic group, monosomy 7, and EVI1 overexpression (P <.01). Patients with SETBP1 overexpression had a significantly shorter overall survival, and the prognosis impact was remarkably poor in patients older than 60 years in both overall survival (P=.015) and event-free survival (P=.015). In summary, our data show a novel leukemogenic mechanism through SETBP1 overexpression; moreover, multivariate analysis confirms the negative prognostic impact of SETBP1 overexpression in AML, especially in elderly patients, where it could be used as a predictive factor in any future clinical trials with PP2A activators.
