Isidro Sánchez-García

Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility.

UNLABELLEDnEarlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5(+/-) leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development.nnnSIGNIFICANCEnThese results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease.

Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.

Extremely low-frequency magnetic fields and risk of childhood leukemia: A risk assessment by the ARIMMORA consortium.

Exposure to extremely low-frequency magnetic fields (ELF-MF) was evaluated in an International Agency for Research on Cancer (IARC) Monographs as possibly carcinogenic to humans in 2001, based on increased childhood leukemia risk observed in epidemiological studies. We conducted a hazard assessment using available scientific evidence published before March 2015, with inclusion of new research findings from the Advanced Research on Interaction Mechanisms of electroMagnetic exposures with Organisms for Risk Assessment (ARIMMORA) project. The IARC Monograph evaluation scheme was applied to hazard identification. In ARIMMORA for the first time, a transgenic mouse model was used to mimic the most common childhood leukemia: new pathogenic mechanisms were indicated, but more data are needed to draw definitive conclusions. Although experiments in different animal strains showed exposure-related decreases of CD8+ T-cells, a role in carcinogenesis must be further established. No direct damage of DNA by exposure was observed. Overall in the literature, there is limited evidence of carcinogenicity in humans and inadequate evidence of carcinogenicity in experimental animals, with only weak supporting evidence from mechanistic studies. New exposure data from ARIMMORA confirmed that if the association is nevertheless causal, up to 2% of childhood leukemias in Europe, as previously estimated, may be attributable to ELF-MF. In summary, ARIMMORA concludes that the relationship between ELF-MF and childhood leukemia remains consistent with possible carcinogenicity in humans. While this scientific uncertainty is dissatisfactory for science and public health, new mechanistic insight from ARIMMORA experiments points to future research that could provide a step-change in future assessments. Bioelectromagnetics. 37:183-189, 2016.

Medical chemistry to spy cancer stem cells from outside the body

Accumulating evidence indicates that cancer is maintained by cancer stem cells (CSC). The goal of molecular imaging is to detect pathologic biomarkers, which can lead to early recognition of cancer, better therapeutic management, and improved monitoring for recurrence. The main focus of this review is to describe the different classes of tracers, contrast agents and dyers, and their putative application to improve cancer stem cells detection and follow-up. Although the in vivo cancer diagnosis has not significantly changed for the past three decades, however, in the future it might be possible to trace all cancer cells, including the cancer stem cells.

Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

The impact of LMO2 expression on cell lineage decisions during T‐cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T‐cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human‐like T‐ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T‐ALL. The resulting T‐ALLs lacked LMO2 and its target‐gene expression, and histologically, transcriptionally, and genetically similar to human LMO2‐driven T‐ALL. We next found that during T‐ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T‐ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre‐mediated activation of Lmo2 at different stages of B‐cell development induces systematically and unexpectedly T‐ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T‐ALL to current therapies.

GEMMs addressing Pax5 loss-of-function in childhood pB-ALL.

Germline mutations in transcription factors, which are implicated in hematopoiesis in general or specifically in B-cell differentiation have recently been described to confer an inherited risk to pB-ALL with often reduced penetrance. Predicting leukemia development, therapy response and long term follow up of mutation carriers is challenging because experience from large patient cohorts and their long term follow up are not available. Genetically Engineered Murine Models (GEMMs) represent a promising approach to create individualized and precise models reproducing the molecular makeup of the human disease. This review focuses on PAX5 loss-of-function and summarizes techniques of murine model generation, available GEMMs, which mimic Pax5 loss-of-function in leukemia development and discusses the challenges and drawbacks of these models. These aspects are discussed in the context of creating a robust model, which serves not only for validation of the relevance of a genomic alteration in pB-ALL but at the same time as a valid preclinical model.

T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology

ABSTRACT Genetic lineage tracing in cell type-specific mouse models of T-cell acute lymphoblastic leukemia (T-ALL) have revealed that tumor cell identity is imposed by expression of the oncogene Lim Domain Only 2 (LMO2), rather than by the target cell phenotype. This approach allowed to identify that secondary genomic alterations, like Notch1 mutations, appeared late and only took place within the thymus during T-ALL development. These concepts are therefore critical for the development of modern therapies aimed at curing T-ALL.

Dnmt1 links BCR-ABLp210 to epigenetic tumor stem cell priming in myeloid leukemia

Research in CVD group is partially supported by FEDER, “Miguel Servet” Grant (CP14/00082 - AES 2013-2016) from the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad), “Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III” (PI17/00167), and by the Lady Tata International Award for Research in Leukaemia 2016–2017. Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791- REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y Leon (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), and by the German Carreras Foundation (DJCLS R13/26). ISG lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. IGR was supported by BES-Ministerio de Economia y Competitividad (BES2013-063789). GRH was supported by FSE-Conserjeria de Educacion de la Junta de Castilla y Leon (CSI001-15).

Comparative dosimetry for children and rodents exposed to extremely low-frequency magnetic fields

We describe a method to correlate E-fields induced by exposure to extremely low frequency magnetic fields in laboratory mice and rats during in vivo experiments to those induced in children. Four different approaches of mapping relative dose rates between humans and rodents are herein proposed and analyzed. Based on these mapping methods and volume averaging guidelines published by the International Commission on Non-Ionizing Radiation Protection (ICNRP) in 2010, maximum and median induced field values for whole body and for tissues of children and rodents were evaluated and compared. Median induced electric fields in children younger than 10 years old are in the range 5.9-8.5u2009V/m per T (±0.4u2009dB). Maximum induced electric fields, generally in the skin, are between 48u2009V/m and 228u2009V/m per T (±4u2009dB). To achieve induced electric fields of comparable magnitude in rodents, external magnetic field must be increased by a factor of 4.0 (±2.6u2009dB) for rats and 7.4 (±1.8u2009dB) for mice. Meanwhile, to achieve comparable magnetic field dose in rodents, ratio is close to one. These induced field dose rates for children and rodents can be used to quantifiably compare experimental data from in vivo studies with data on exposure of children from epidemiological studies, such as for leukemia. Bioelectromagnetics. 37:310-322, 2016.