T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology.
Ontology highlight
ABSTRACT:
SUBMITTER: Rodriguez-Hernandez G
PROVIDER: S-EPMC6150050 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology.
Rodríguez-Hernández Guillermo G Bhatia Sanil S Vicente-Dueñas Carolina C Borkhardt Arndt A Hauer Julia J Sánchez-García Isidro I
Molecular & cellular oncology 20180807 4
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 <i>Lim Domain Only 2</i> (<i>LMO2)</i>, rather than by the target cell phenotype. This approach allowed to identify that secondary genomic alterations, like <i>Notch1</i> mutations, appeared late and only took place within the thymus during T-ALL development. These concepts are therefore critical for the developm ...[more]
Similar Datasets
Project description:BackgroundDespite recent advances in research, there are still critical lacunae in our basic understanding of the cause, pathogenesis, and natural history of many cancers, especially heterogeneity in patient response to drugs and mediators in the transition from malignant to invasive phenotypes. The explication of the pathogenesis of cancer has been constrained by limited access to patient samples, tumor heterogeneity and lack of reliable biological models. Amelioration in cancer treatment depends on further understanding of the etiologic, genetic, biological, and clinical heterogeneity of tumor microenvironment. Patient-derived organoids recapitulate the basic features of primary tumors, including histological complexity and genetic heterogeneity, which is instrumental in predicting patient response to drugs.MethodsHuman iPSCs from healthy donors, breast and ovarian cancer patients were successfully differentiated towards isogenic hepatic, cardiac, neural and endothelial lineages. Multicellular organoids were established using Primary cells isolated from tumor tissues, histologically normal tissues adjacent to the tumors (NATs) and adipose tissues (source of Mesenchymal Stem Cells) from ovarian and breast cancer patients. Further these organoids were propagated and used for drug resistance/sensitivity studies.ResultsOvarian and breast cancer patients' organoids showed heterogeneity in drug resistance and sensitivity. iPSCs-derived cardiomyocytes, hepatocytes and neurons showed donor-to-donor variability of chemotherapeutic drug sensitivity in ovarian cancer patients, breast cancer patients and healthy donors.ConclusionWe report development of a novel integrated platform to facilitate clinical decision-making using the patient's primary cells, iPSCs and derivatives, to clinically relevant models for oncology research.
| S-EPMC10362580 | biostudies-literature
Project description:PURPOSE:Precision oncology is hindered by the lack of decision support for determining the functional and therapeutic significance of genomic alterations in tumors and relevant clinically available options. To bridge this knowledge gap, we established a Precision Oncology Decision Support (PODS) team that provides annotations at the alteration-level and subsequently determined if clinical decision-making was influenced. METHODS:Genomic alterations were annotated to determine actionability based on a variant's known or potential functional and/or therapeutic significance. The medical records of a subset of patients annotated in 2015 were manually reviewed to assess trial enrollment. A web-based survey was implemented to capture the reasons why genotype-matched therapies were not pursued. RESULTS:PODS processed 1,669 requests for annotation of 4,084 alterations (2,254 unique) across 49 tumor types for 1,197 patients. 2,444 annotations for 669 patients included an actionable variant call: 32.5% actionable, 9.4% potentially, 29.7% unknown, 28.4% non-actionable. 66% of patients had at least one actionable/potentially actionable alteration. 20.6% (110/535) patients annotated enrolled on a genotype-matched trial. Trial enrolment was significantly higher for patients with actionable/potentially actionable alterations (92/333, 27.6%) than those with unknown (16/136, 11.8%) and non-actionable (2/66, 3%) alterations (p=0.00004). Actionable alterations in PTEN, PIK3CA, and ERBB2 most frequently led to enrollment on genotype-matched trials. Clinicians cited a variety of reasons why patients with actionable alterations did not enroll on trials. CONCLUSION:Over half of alterations annotated were of unknown significance or non-actionable. Physicians were more likely to enroll a patient on a genotype-matched trial when an annotation supported actionability. Future studies are needed to demonstrate the impact of decision support on trial enrollment and oncologic outcomes.
| S-EPMC6179148 | biostudies-other
Project description:BackgroundTherapeutic decision-making in oncology is a complex process because physicians must consider many forms of medical data and protocols. Another challenge for physicians is to clearly communicate their decision-making process to patients to ensure informed consent. Computer-based decision tools have the potential to play a valuable role in supporting this process.ObjectiveThis systematic review aims to investigate the extent to which computer-based decision tools have been successfully adopted in oncology consultations to improve patient-physician joint therapeutic decision-making.MethodsThis review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist and guidelines. A literature search was conducted on February 4, 2021, across the Cochrane Database of Systematic Reviews (from 2005 to January 28, 2021), the Cochrane Central Register of Controlled Trials (December 2020), MEDLINE (from 1946 to February 4, 2021), Embase (from 1947 to February 4, 2021), Web of Science (from 1900 to 2021), Scopus (from 1969 to 2021), and PubMed (from 1991 to 2021). We used a snowball approach to identify additional studies by searching the reference lists of the studies included for full-text review. Additional supplementary searches of relevant journals and gray literature websites were conducted. The reviewers screened the articles eligible for review for quality and inclusion before data extraction.ResultsThere are relatively few studies looking at the use of computer-based decision tools in oncology consultations. Of the 4431 unique articles obtained from the searches, only 10 (0.22%) satisfied the selection criteria. From the 10 selected studies, 8 computer-based decision tools were identified. Of the 10 studies, 6 (60%) were conducted in the United States. Communication and information-sharing were improved between physicians and patients. However, physicians did not change their habits to take advantage of computer-assisted decision-making tools or the information they provide. On average, the use of these computer-based decision tools added approximately 5 minutes to the total length of consultations. In addition, some physicians felt that the technology increased patients' anxiety.ConclusionsOf the 10 selected studies, 6 (60%) demonstrated positive outcomes, 1 (10%) showed negative results, and 3 (30%) were neutral. Adoption of computer-based decision tools during oncology consultations continues to be low. This review shows that information-sharing and communication between physicians and patients can be improved with the assistance of technology. However, the lack of integration with electronic health records is a barrier. This review provides key requirements for enhancing the chance of success of future computer-based decision tools. However, it does not show the effects of health care policies, regulations, or business administration on physicians' propensity to adopt the technology. Nevertheless, it is important that future research address the influence of these higher-level factors as well.Trial registrationPROSPERO International Prospective Register of Systematic Reviews CRD42021226087; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226087.
| S-EPMC8579220 | biostudies-literature
Project description:The goal of this study is compare the transcriptome profilling of different genetically engineered mouse models to the Human scenerio, in order to better understand the role of Lmo2 expression on cell lineage decision during T-cell leukemogenesis. Results: The up-regulated Rosa26-Lmo2+Sca1-Cre and Sca1-Lmo2 signatures shows a significant enrichment in the human T-ALL group. Conclusion: The similarity between Rosa26-Lmo2+Sca1-Cre and Human T-ALL signature is in accordance to the Human T-ALL situation wherein the expression of LMO2 is present throughout in tumor cells.
2018-05-01 | GSE113864 | GEO
Project description: Not available
| S-EPMC10308051 | biostudies-literature
Project description:With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719-31. ©2018 AACR.
| S-EPMC6004235 | biostudies-literature
Project description:BCR-ABL, an oncogenic fusion gene, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Oncogenic signaling induces oncogene-induced senescence and senescence-associated secretory phenotype (SASP), which is characterized by enhanced production of various cytokines. BCR-ABL gene transduction confers senescent phenotype in vitro; however, the in vivo relevance of senescence has not been explored in this context. Transplantation of BCR-ABL-expressing hematopoietic stem/progenitor cells caused CML in mice with an increase in bone marrow BCR-ABL+CD41+CD150+ leukemic megakaryocyte-lineage (MgkL) cells, which exhibited enhanced senescence-associated β-galactosidase staining and increased expression of p16 and p21, key molecules that are crucially involved in senescence. Moreover, knockout of p16 and p21 genes reduced both BCR-ABL-induced abnormal megakaryopoiesis and the maintenance of CML cell leukemogenic capacity, as evidenced by attenuated leukemogenic capacity at secondary transplantation. The expression of transforming growth factor-β1 (TGF-β1), a representative SASP molecule, was enhanced in the leukemic MgkL cells, and TGF-β1 inhibition attenuated CML cell leukemogenic capacity both in vitro and in vivo. Furthermore, BCR-ABL-expressing MgkL cells displayed enhanced autophagic activity, and autophagy inhibition reduced bone marrow MgkL cell number and prolonged the survival of CML mice, which had transiently received the tyrosine kinase inhibitor, imatinib, earlier. Thus, BCR-ABL induced the expansion of senescent leukemic MgkL cells, which supported CML leukemogenesis by providing TGF-β1.
| S-EPMC7757005 | biostudies-literature
Project description:Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis. Unlike monogenic disorders, a more complicated series of genetic mutations are believed to be responsible for MPN with various degrees of thromboembolic and bleeding complications. Thrombosis is one of the early manifestations in patients with MPN. To date, the driver genes responsible for MPN include JAK2, CALR, MPL, TET2, ASXL1, and MTHFR. Affords have been done to elucidate these mutations and the incidence of thromboembolic events. Several lines of evidence indicate that mutations in JAK2, MPL, TET2 and ASXL1 gene and polymorphisms in several clotting factors (GPIa, GPIIa, and GPIIIa) are associated with the occurrence and prevalence of thrombosis in MPN patients. Some polymorphisms within XRCC1, FBG, F2, F5, F7, F12, MMP9, HPA5, MTHFR, SDF-1, FAS, FASL, TERT, ACE, and TLR4 genes may also play a role in MPN manifestation. This review aims to provide an insightful overview on the genetic perspective of thrombotic complications in patients with MPN.
| S-EPMC9818412 | biostudies-literature
Project description:Selective estrogen receptor modulators (SERMs) reduce breast cancer risk. Adoption of SERMs as prevention medication remains low. This is the first study to quantify social, cultural, and psychologic factors driving decision making regarding SERM use in women counseled on breast cancer prevention options. A survey study was conducted with women counseled by a health care provider (HCP) about SERMs. A statistical comparison of responses was performed between those who decided to use and those who decided not to use SERMs. Independent factors associated with the decision were determined using logistic regression. Of 1,023 participants, 726 made a decision: 324 (44.6%) decided to take a SERM and 402 (55.4%) decided not to. The most important factor for deciding on SERM use was the HCP recommendation. Other characteristics associated with the decision included attitudes and perceptions regarding medication intake, breast cancer worry, trust in HCP, family members with blood clots, and others' experiences with SERMs. The odds of SERM intake when HCP recommended were higher for participants with a positive attitude toward taking medications than for those with a negative attitude (Pinteraction = 0.01). This study highlights the importance of social and cultural aspects for SERM decision making, most importantly personal beliefs and experiences. HCPs' recommendations play a statistically significant role in decision making and are more likely to be followed if in line with patients' attitudes. Results indicate the need for developing interventions for HCPs that not only focus on the presentation of medical information but, equally as important, on addressing patients' beliefs and experiences. Cancer Prev Res; 10(11); 625-34. ©2017 AACRSee related editorial by Crew, p. 609.
| S-EPMC5848501 | biostudies-literature
Project description:Breast cancer is the most common cancer in women, impacting 2.1 million women each year. The number of publications on BC is much higher than for any other type of tumor, as well as the number of clinical trials. One of the consequences of all this information is reflected in the number of approved drugs. This review aims to discuss the impact of technological advances in the diagnosis, treatment and decision making of breast cancer and the prospects for the next 10 years. Currently, the literature has described personalized medicine, but what will the treatment be called for in the coming years?
| S-EPMC8703478 | biostudies-literature