Targeting Pre-Leukemic Stem Cells in T-Acute Lymphoblastic Leukemia
| العنوان: | Targeting Pre-Leukemic Stem Cells in T-Acute Lymphoblastic Leukemia |
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| المؤلفون: | Dominique Geoffrion, Bastien Gerby, Milena Kosic, Véronique Litalien, Joel Ryan, Anne Marinier, Philippe P. Roux, André Haman, Elizabeth Ottoni, Julianne Ouellette, Benjamin H. Kwok, Jalila Chagraoui, Paul S. Maddox, Geneviève Lavoie, Jana Krosl, Mathieu Tremblay, Guy Sauvageau, Diogo F.T. Veiga, Trang Hoang, Josée Hébert, Iman Fares |
| المصدر: | ResearcherID |
| بيانات النشر: | American Society of Hematology, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | T cell, Immunology, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, T Acute Lymphoblastic Leukemia, Haematopoiesis, Leukemia, medicine.anatomical_structure, Acute lymphocytic leukemia, medicine, Cancer research, Progenitor cell, Stem cell, Reprogramming |
| الوصف: | Current chemotherapy of pediatric T cell acute lymphoblastic leukemia (T-ALL) efficiently reduces the tumor mass with, however, undesirable long term consequences and remains ineffective in adolescent and adult T-ALL. Furthermore, relapse can be caused by pre-leukemic stem cells (pre-LSCs) that were spared by current protocols and evolved to malignancy. A distinctive characteristic of pre-LSCs is their critical dependence on interactions with the microenvironment for survival, which guided our strategy to target pre-LSCs using niche-based screening assays. Using transgenic mouse models that closely reproduce the human disease, we showed that the SCL/TAL1 and LMO1 oncogenic transcription factors establish a pre-leukemic state by reprogramming normal pro-T cells into aberrantly self-renewing pre-LSCs (Gerby et al. PloS Genetics, 2014). We now provide direct evidence that pre-LSCs are much less chemosensitive than leukemic blasts to current drugs, due to a distinctive lower proliferative state as assessed by real-time imaging in a competitive assay. We therefore designed a robust protocol for high-throughput screening (HTS) of compounds targeting primary pre-LSCs that are maintained on stromal cells engineered for optimal NOTCH1 activation to mimick the thymic microenvironement. The multiparametric readout takes into account the intrinsic complexity of primary cells to specifically monitor pre-LSCs. We screened a targeted library of 1904 compounds and identified UM0119979 that disrupts both cell autonomous and non-cell autonomous pathways: UM0119979 abrogates pre-LSC viability and self-renewal activity in vivo by specifically inhibiting the translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remain functional. Moreover, in vivo administration of UM0119979 efficiently reduced the leukemia propagating activity of primary human T-ALL samples in xenografted mice. Finally, in addition to SCL-LMO-induced T-ALL, our results reveal a novel possibility of therapeutic intervention in MYC-dependent hematologic malignancies. In summary, our screening assay, built on the genetic dependencies of pre-LSCs, revealed their vulnerabilities to compounds that inhibit both the primary oncogenes and non-cell autonomous pathways triggered by the microenvironment. The results illustrate how recapitulating tissue-like properties of primary cells in high throughput screening is a promising avenue for innovation in cancer chemotherapy. Disclosures No relevant conflicts of interest to declare. |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d49aba938f5a9febef5d412d507f0ea1 https://doi.org/10.1182/blood.v128.22.527.527 |
| رقم الأكسشن: | edsair.doi.dedup.....d49aba938f5a9febef5d412d507f0ea1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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