Investigating the response of paediatric leukaemia-propagating cells to BCL-2 inhibitors

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.

Automated summary

Relapse of paediatric acute lymphoblastic leukaemia (ALL) may occur due to the persistence of resistant cells with leukaemia-propagating ability (LPC). Response to BCL-2 inhibitors navitoclax and venetoclax varies in LPC subpopulations from B-cell precursor (BCP) and T-cell ALL cases, with navitoclax showing more efficacy. Some LPC are resistant to BCL-2 inhibitors, indicating the need for combination therapy with other therapeutics for sustained remission.