Abstract
SummaryRelapse 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.
Highlights
We demonstrated that the frequency of leukaemia-propagating cells (LPC) was often higher in CD34+/CD19À and CD34À subpopulations than in CD34+/CD19+ cells in B-cell precursor (BCP)
Eleven BCP-acute lymphoblastic leukaemia (ALL) cases were sensitive to navitoclax with a mean IC50 of 41 nmol/l
There was no significant difference in responses between measurable residual disease (MRD) low, intermediate or high risk groups (P = 0Á52 for navitoclax and P = 0Á37 for venetoclax)
Summary
BM cells from children (median age, 7 years; range, 2–17) with BCP- (n = 20) and T-ALL (n = 11) at diagnosis or relapse were collected with approval of University Hospitals Bristol NHS Trust (Table I). Mononuclear cells were cryopreserved as described.[15,16] Viability on thawing was 69Á6 Æ 16Á1% (ALL) and 73Á0 Æ 9Á3% (normal) samples. BCP-ALL cells were stained with antibodies against CD34 (clone 8G12) and CD19 (clone 4G7). T-ALL cells were stained with anti-CD34 and anti-CD7 (clone M-T701). NBM and CB samples were stained with anti-CD34 and anti-CD38 (clone HB7, all BD Biosciences, Oxford, UK). Cells were stained with propidium iodide (PI; Miltenyi Biotec, Bisley, UK) to exclude dead cells and live cells were sorted using a Becton Dickinson Influx cell sorter with BD sortware 1.2.0 (BD Biosciences, see Figure S1)
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