Investigating the response of paediatric leukaemia‐propagating cells to BCL‐2 inhibitors
| Autor: | Phoebe E I Dace, John Moppett, Benjamin C Ede, Paraskevi Diamanti, William J Barendt, Jeremy Hancock, Allison Blair, Charlotte V. Cox |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Adolescent Microarray CD34 Antineoplastic Agents Precursor T-Cell Lymphoblastic Leukemia-Lymphoma CD19 Venetoclax 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Precursor B-Cell Lymphoblastic Leukemia-Lymphoma hemic and lymphatic diseases BCL‐2 Humans Medicine Child paediatric ALL NSG Sulfonamides Aniline Compounds Navitoclax biology business.industry Haematological Malignancy ‐ Biology Hematology Bridged Bicyclo Compounds Heterocyclic In vitro Blot LPC Treatment Outcome Proto-Oncogene Proteins c-bcl-2 chemistry Paediatric ALL Child Preschool 030220 oncology & carcinogenesis biology.protein Cancer research Female lipids (amino acids peptides and proteins) ALL business Research Paper 030215 immunology |
| Zdroj: | British Journal of Haematology Diamanti, P, Ede, B C, Dace, P E I, J Barendt, W, Cox, C V, Hancock, J P, Moppett, J P & Blair, A 2020, ' Investigating the response of paediatric leukaemia propagating cells to BCL-2 inhibitors ', British Journal of Haematology . https://doi.org/10.1111/bjh.16773 |
| ISSN: | 1365-2141 0007-1048 |
| Popis: | Summary Relapse of paediatric acute lymphoblastic leukaemia (ALL) may occur due to persistence of resistant cells with leukaemia‐propagating ability (LPC). In leukaemia, the balance of B‐cell lymphoma‐2 (BCL‐2) family proteins is disrupted, promoting survival of malignant cells and possibly LPC. A direct comparison of BCL‐2 inhibitors, navitoclax and venetoclax, was undertaken on LPC subpopulations from B‐cell precursor (BCP) and T‐cell ALL (T‐ALL) cases in vitro and in vivo. Responses were compared to BCL‐2 levels detected by microarray analyses and Western blotting. In vitro, both drugs were effective against most BCP‐ALL LPC, except CD34−/CD19− cells. In contrast, only navitoclax was effective in T‐ALL and CD34−/CD7− LPC were resistant to both drugs. In vivo, navitoclax was more effective than venetoclax, significantly improving survival of mice engrafted with BCP‐ and T‐ALL samples. Venetoclax was not particularly effective against T‐ALL cases in vivo. The proportions of CD34+/CD19−, CD34−/CD19− BCP‐ALL cells and CD34−/CD7− T‐ALL cells increased significantly following in vivo treatment. Expression of pro‐apoptotic BCL‐2 genes was lower in these subpopulations, which may explain the lack of sensitivity. These data demonstrate that some LPC were resistant to BCL‐2 inhibitors and sustained remission will require their use in combination with other therapeutics. |
| Databáze: | OpenAIRE |
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