TY - JOUR
T1 - Glucocorticoid sensitisation in Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia by the pan-BCL-2 family inhibitors gossypol and AT-101
AU - Spijkers-Hagelstein, Jill A.P.
AU - Schneider, Pauline
AU - Pinhanços, Sandra Mimoso
AU - Garrido Castro, Patricia
AU - Pieters, Rob
AU - Stam, Ronald W.
N1 - Funding Information:
The authors gratefully thank all the members and participating hospitals of the INTERFANT-99 study groups for supporting our research by generously providing leukaemic samples. This study was funded by KIKA (stichting Kinderen Kankervrij) (J.A.P.S-H.). R.W.S. was financially supported by the Dutch Cancer Society (KWF Kankerbestrijding, project nr. UVA2008-4265 ). The institutions funding this research did not participate in study design, data collection, data analysis, data interpretation or writing of the report. All authors had full access to all the data at all time, and shared final responsibility for the decision to submit for publication.
PY - 2014/6
Y1 - 2014/6
N2 - Aim of the study Resistance to glucocorticoids (GCs) remains a major problem in the treatment of infants with acute lymphoblastic leukaemia (ALL) carrying Mixed Lineage Leukaemia (MLL) translocations. Despite intensive research, the mechanism(s) underlying GC resistance remain poorly understood. Recent studies suggested an important role for the pro-survival BCL-2 family member MCL1 in GC resistance in MLL-rearranged ALL. Methods We exposed GC-resistant MLL-rearranged SEMK2 cells to potent MCL1-inhibiting agents, including gossypol, AT-101, rapamycin, SU9516 and obatoclax (GX15-070) and determined GC sensitisation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays. Using Western blotting we analysed the protein expression of most BCL-2 family members in MLL-rearranged SEMK2 cells after treatment with potent MCL-1 inhibiting agents. Results Only gossypol and its synthetic analogue AT-101 induced GC sensitivity in MLL-rearranged ALL cells. Remarkably, the GC-sensitising effects of gossypol and AT-101 appeared not to be mediated by down-regulation MCL1 or other anti-apoptotic BCL-2 family members, but rather involved up-regulation of multiple pro-apoptotic BCL-2 family members, in particular that of BIM and BID. Concluding remarks In conclusion, gossypol and AT-101 induce GC sensitivity in MLL-rearranged ALL cells, most likely mediated by the activation of BID and BIM without the necessity to down-regulate anti-apoptotic BCL-2 family members like MCL1. Hence, co-administration of either gossypol or AT-101 during GC treatment of GC-resistant MLL-rearranged ALL patients may overcome GC resistance and improve prognosis in this high-risk childhood leukaemia.
AB - Aim of the study Resistance to glucocorticoids (GCs) remains a major problem in the treatment of infants with acute lymphoblastic leukaemia (ALL) carrying Mixed Lineage Leukaemia (MLL) translocations. Despite intensive research, the mechanism(s) underlying GC resistance remain poorly understood. Recent studies suggested an important role for the pro-survival BCL-2 family member MCL1 in GC resistance in MLL-rearranged ALL. Methods We exposed GC-resistant MLL-rearranged SEMK2 cells to potent MCL1-inhibiting agents, including gossypol, AT-101, rapamycin, SU9516 and obatoclax (GX15-070) and determined GC sensitisation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays. Using Western blotting we analysed the protein expression of most BCL-2 family members in MLL-rearranged SEMK2 cells after treatment with potent MCL-1 inhibiting agents. Results Only gossypol and its synthetic analogue AT-101 induced GC sensitivity in MLL-rearranged ALL cells. Remarkably, the GC-sensitising effects of gossypol and AT-101 appeared not to be mediated by down-regulation MCL1 or other anti-apoptotic BCL-2 family members, but rather involved up-regulation of multiple pro-apoptotic BCL-2 family members, in particular that of BIM and BID. Concluding remarks In conclusion, gossypol and AT-101 induce GC sensitivity in MLL-rearranged ALL cells, most likely mediated by the activation of BID and BIM without the necessity to down-regulate anti-apoptotic BCL-2 family members like MCL1. Hence, co-administration of either gossypol or AT-101 during GC treatment of GC-resistant MLL-rearranged ALL patients may overcome GC resistance and improve prognosis in this high-risk childhood leukaemia.
KW - Acute lymphoblastic leukaemia
KW - Gossypol and AT-101
KW - MLL translocation
KW - Prednisolone sensitivity
UR - http://www.scopus.com/inward/record.url?scp=84901188207&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2014.03.011
DO - 10.1016/j.ejca.2014.03.011
M3 - Article
C2 - 24703900
AN - SCOPUS:84901188207
SN - 0959-8049
VL - 50
SP - 1665
EP - 1674
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 9
ER -