Abstract Oncogene addiction is the dependence seen in some types of cancer cells on the presence or activity of an oncogene. Chronic myeloid leukaemia (CML) is driven by the BCR‐ABL1 oncogene. CML has become a paradigm for targeted therapies, as the disease is effectively managed in most patients by BCR‐ABL1 inhibitors. Although the symptom‐causing leukaemic progenitor cells depend on the kinase activity of BCR‐ABL1 for survival, the more primitive leukaemia stem cells (LSCs) responsible for disease maintenance and relapse are not dependent on the BCR‐ABL1 oncogene and lie dormant in the bone marrow of patients during treatment. The advances in knowledge achieved through the study of CML LSCs indicate that cancer stem cells (CSCs), which underlie many different cancers, may not display oncogene addiction in the classical sense. This provides yet another obstacle to the efforts to cure cancers using targeted therapies. To eradicate these CSCs and discover ways to truly cure CML and other CSC‐driven cancers, we must investigate them for their unique dependencies. Key Concepts Oncogene addiction refers to the dependence of some types of cancer cells on the presence or activity of an oncogene. Cancer researchers are working to identify sources of oncogene addiction, as they represent attractive therapeutic targets. Chronic myeloid leukaemia progenitor cells are dependent on BCR‐ABL1 oncogenic kinase activity for their survival. Targeting the ‘addictive’ BCR‐ABL1 oncoprotein has proved to be a successful therapeutic strategy for managing chronic myeloid leukaemia. Some cancers are maintained by self‐renewing multipotent cancer stem cells. Cancer stem cells have demonstrated the ability to escape oncogene addiction, for example, in chronic myeloid leukaemia. Activation of alternative survival pathways may protect cancer stem cells from therapeutic targeting of proteins encoded by oncogenes. Combining high‐throughput and single‐cell technologies could be a powerful strategy to investigate oncogene dependencies of cancer stem cells.
Abstract We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared with FMC63 CAR T cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B cells present in the manufacture.
Abstract We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and anti-tumour efficacy compared to the high-affinity (FMC63 based) CAR used in Tisagenlecleucel, in pre-clinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a Phase I clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T-cells, we performed a systematic in vitro characterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes occurring in T-cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.
Abstract The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed “minimal residual disease”. The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin − CD34 + CD38 − CD90 + CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93 − CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin − CD34 + CD38 − CD90 + CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.
Alström syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal dystrophy, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and multi-organ fibrosis, characteristic in kidneys and liver. Depletion of the protein encoded by ALMS1 has been associated with the alteration of different processes regulated via the primary cilium, such as the NOTCH or TGF-β signalling pathways. However, the cellular impact of these deregulated pathways in the absence of ALMS1 remains unknown.
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