Cancer Stem Cells as a Result of a Reprogramming-Like Mechanism

Open Access: under CC BY-NCSA 3.0 license.Research in our groups is partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (Proyecto Biomedicina 2009-2010 to ISG, and Proyecto Biomedicina 2010-2011 to CVD), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007- 0017) to ISG, by NIH grant (R01 CA109335-04A1) to ISG, by Sandra Ibarra Foundation to ISG, and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon to ISG and JJC.Peer reviewe

Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice

This work is licensed under a Creative Commons Attribution 3.0 License.The telomerase protein is constitutively activated in malignant cells from many patients with cancer, including the chronic myeloid leukemia (CML), but whether telomerase is essential for the pathogenesis of this disease is not known. Here, we used telomerase deficient mice to determine the requirement for telomerase in CML induced by BCR-ABL in mouse models of CML. Loss of one telomerase allele or complete deletion of telomerase prevented the development of leukemia induced by BCR-ABL. However, BCR-ABL was expressed and active in telomerase heterozygous and null leukemic hematopoietic stem cells. These results demonstrate that telomerase is essential for oncogene-induced reprogramming of hematopoietic stem cells in CML development and validate telomerase and the genes it regulates as targets for therapy in CML.Research in ISG group was partially supported by FEDER and by MICINN (SAF2009-08803 to ISG), by Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009-2010), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, and the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and by Proyecto en Red de Investigación en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER program. ISG is an API lab of the EuroSyStem project.Peer Reviewe

HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block

Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

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

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Reprogramación tumoral en neoplasias linfoides

Trabajo presentado por la doctoranda Dña. Isabel Romero Camarero para optar al Título de Doctor por la Universidad de Salamanca que ha sido realizado en el Instituto de Biología Molecular y Celular del Cáncer.El cáncer es un término genérico que designa un amplio grupo de enfermedades que pueden afectar a cualquier parte del organismo. En el año 2012, se cobró la vida de 8.000.000 personas, y es que, a pesar de todos los esfuerzos realizados a conocer la biología del cáncer, la supervivencia global no se ha visto incrementada de manera notoria y, en la mayoría de los casos se debe a una detección precoz de la enfermedad. Nuestro grupo de investigación está interesado en estudiar las etapas iniciales del cáncer, que van a convertir una célula pretumoral en una célula madre cancerígena. Una célula madre cancerígena es una célula neoplásica con características de célula madre, esto es, autorrenovación y capacidad de diferenciación, capaz de regenerar toda la diversidad celular presente en el tumor. La existencia de las células madre cancerígenas explicaría por qué algunos pacientes, tras un período de remisión inicial, sufren recaídas. Estas células madre cancerígenas serían las responsables de regenerar toda la masa tumoral de células. Sin embargo, no debemos confundir la célula madre cancerígena con la célula origen del cáncer, que es la célula donde va a tener lugar el primer evento oncogénico. En este contexto debemos hablar de la reprogramación tumoral, que es el proceso por el cual un evento oncogénico reprogramaría una célula, en este caso la célula origen del cáncer mediante alteraciones epigenéticas en su transcriptoma, estableciendo en ella un programa de diferenciación patológico que culminaría en el desarrollo de una masa tumoral, donde el oncogén ya no sería necesario ni para la progresión ni para el mantenimiento del cáncer. Nosotros quisimos estudiar la reprogramación tumoral en el contexto del linfoma difuso de células B grandes mediante la sobreexpresión de HGAL y en la génesis de leucemias linfoblásticas T tras la sobreexpresión de Lmo2.La investigación en nuestro laboratorio está financiada parcialmente por FEDER y por el MICINN (SAF2012-32810), por el NIH (R01 CA109335-04A1), por la Junta de Castilla y León (BIO/SA06/13), por el proyecto ARIMMORA (FP7-ENV-2011, European Union Seventh Framework Program) y por la Fundación Carreras (DJCLS R13/26). Nuestro laboratorio es miembro del EuroSyStem y la Red DECIDE, financiadas por el programa FP7 de la Unión Europea. Durante la realización de este proyecto doctoral he disfrutado de una beca predoctoral del Programa de Formación del Profesorado Universitario (FPU) del Ministerio de Educación, Cultura y Deporte con referencia AP2009-3464 y de una beca con cargo a la investigación (Contrato Art.83 LOU (GRIFOLS-USAL)) con referencia LFI2.Peer Reviewe

Reprogramación tumoral en neoplasmas linfoides

[ES]El cáncer es un término genérico que designa un amplio grupo de enfermedades que pueden afectar a cualquier parte del organismo. En el año 2012, se cobró la vida de 8.000.000 personas, y es que, a pesar de todos los esfuerzos realizados a conocer la biología del cáncer, la supervivencia global no se ha visto incrementada de manera notoria y, en la mayoría de los casos se debe a una detección precoz de la enfermedad. Nuestro grupo de investigación está interesado en estudiar las etapas iniciales del cáncer, que van a convertir una célula pretumoral en una célula madre cancerígena. Una célula madre cancerígena es una célula neoplásica con características de célula madre, esto es, autorrenovación y capacidad de diferenciación, capaz de regenerar toda la diversidad celular presente en el tumor. La existencia de las células madre cancerígenas explicaría por qué algunos pacientes, tras un período de remisión inicial, sufren recaídas. Estas células madre cancerígenas serían las responsables de regenerar toda la masa tumoral de células. Sin embargo, no debemos confundir la célula madre cancerígena con la célula origen del cáncer, que es la célula donde va a tener lugar el primer evento oncogénico. En este contexto debemos hablar de la reprogramación tumoral, que es el proceso por el cual un evento oncogénico reprogramaría una célula, en este caso la célula origen del cáncer mediante alteraciones epigenéticas en su transcriptoma, estableciendo en ella un programa de diferenciación patológico que culminaría en el desarrollo de una masa tumoral, donde el oncogén ya no sería necesario ni para la progresión ni para el mantenimiento del cáncer. Nosotros quisimos estudiar la reprogramación tumoral en el contexto del linfoma difuso de células B grandes mediante la sobreexpresión de HGAL y en la génesis de leucemias linfoblásticas T tras la sobreexpresión de Lmo2

Understanding telomerase in cancer stem cell biology

Editorial.Peer Reviewe

Acute lymphoblastic leukemia and developmental biology: A crucial interrelationship

This is an open access article.The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidences supporting these new points of view. Furthermore, in the case of B-cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research, and discuss their interrelationships and their implications for our understanding of the biology of the disease. © 2011 Landes Bioscience.Research in C.C. lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI080164), CSIC P.I.E., 200920I055 and 201120E060, from the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and from an institutional grant from the “Fundación Ramón Areces.” Research in I.S.G. group was partially supported by FEDER and by MICINN (SAF2009-08803 to I.S.G.), by Junta de Castilla y León (REF. CSI007A11-2 and Proyecto Biomedicina 2009–2010), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), by Sandra Ibarra Foundation, by Group of Excellence Grant (GR15) from Junta de Castilla y Leon, and the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program) and by Proyecto en Red de Investigación en Celulas Madre Tumorales en Cancer de Mama, supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER program. I.S.G. is an API lab of the EuroSyStem project. E.C.S. and M.B.D. are recipients of JAE-predoc fellowships from CSIC. I.R.C. is recipient of a FPU fellowship from MICINN. E.C.S. is recipient of a “Residencia de Estudiantes” fellowship.Peer Reviewe