Development of the first geldanamycin-based HSP90 degraders

Despite the early clinical promise, adverse events such as acquired resistance and dose-limiting toxicities have barred the widespread use of HSP90 inhibitors as anticancer drugs. A new approach involving proteolysis-targeting chimeras (PROTACs) to degrade the protein instead of inhibiting it may overcome these problems. In this work, we describe the design, synthesis, and evaluation of cereblon-recruiting geldanamycin-based HSP90 degraders based on the PROTAC technology. Our best degrader, 3a, effectively decreased HSP90α and HSP90β levels in cells utilizing the ubiquitin–proteasome pathway

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.J.H. has been supported by the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951), the German Jose Carreras Leukemia Foundation (DJCLS 02R/2016), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Joint funding (Targeting MYC L*10), the Kinderkrebsstiftung (2016/17), and the “Elterninitiative Kinderkrebsklinik e.V. Düsseldorf”. SG has been supported by a scholarship of the Hochschule Bonn-Rhein-Sieg. AB has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. 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 León (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente, and by the ARIMMORA project (European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). ISG Lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. AB and ISG have been supported by the German Carreras Foundation (DJCLS R13/26). IGR was supported by BES-Ministerio de Economía y Competitividad (BES-2013-063789). AML and GRH were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13, CSI001-15). 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 Economía 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

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

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

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

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.This work was supported by the the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951); German Carreras Foundation; [DJCLS 02R/2016]; the Kinderkrebsstiftung (2016/17); Elterninitiative Kinderkrebsklinik e.V. Düsseldorf; German Children’s Cancer Foundation; Federal Ministry of Education and Research; FEDER; MINECO; [SAF2012-32810]; [SAF2015-64420-R]; [SAF2014-57791-REDC]; Junta de Castilla y León; [BIO/SA51/15]; [CSI001U14]; [UIC-017]; [CSI001U16]; European Union; German Carreras Foundation; [DJCLS R13/26]; FSE-Conserjería de Educación de la Junta de Castilla y León; [CSI001-15]; FEDER, “Miguel Servet”; [CP14/00082 - AES 2013-2016]; Instituto de Salud Carlos III (Ministerio de Economía y Competitividad); Fondo de Investigaciones Sanitarias/ Instituto de Salud Carlos III; [PI17/00167]; Lady Tata International Award for Research in Leukaemia 2016-2017

Interleukin-2-Inducible T-Cell Kinase Deficiency—New Patients, New Insight?

Patients with primary immunodeficiency can be prone to severe Epstein–Barr virus (EBV) associated immune dysregulation. Individuals with mutations in the interleukin-2-inducible T-cell kinase (ITK) gene experience Hodgkin and non-Hodgkin lymphoma, EBV lymphoproliferative disease, hemophagocytic lymphohistiocytosis, and dysgammaglobulinemia. In this review, we give an update on further reported patients. We believe that current clinical data advocate early definitive treatment by hematopoietic stem cell transplantation, as transplant outcome in primary immunodeficiency disorders in general has gradually improved in recent years. Furthermore, we summarize experimental data in the murine model to provide further insight of pathophysiology in ITK deficiency

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence

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.J.H. has been supported by the German Children’s Cancer Foundation (110997) and from the “Forschungskommission” of the medical faculty of the Heinrich Heine University and the “Strategischer Forschungsfond” of the Heinrich-Heine-University. A.B. has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. A.B. has been supported by the German Carreras Foundation (DJCLS R13/26). Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), National Institutes of Health grant (R01 CA109335-04A1), Junta de Castilla y León (BIO/SA32/14, BIO/SA51/15 and CSI001U14), and the Fundacion Inocente Inocente. Research at CC's lab is partially supported by FEDER, ISCIII (PI13/00160 and PI14/00025) and Fundación Inocente Inocente.Peer Reviewe