Glucocorticoid sensitisation in Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia by the pan-BCL-2 family inhibitors gossypol and AT-101.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
Jill A P
JA
Spijkers-Hagelstein
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
Pauline
P
Schneider
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
Sandra Mimoso
SM
Pinhanços
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
Patricia
P
Garrido Castro
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
Rob
R
Pieters
Department of Paediatric Oncology/Haematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. Electronic address: r.stam@erasmusmc.nl.
Ronald W
RW
Stam
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D023061:Gene Order / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use*; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007223:Infant; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy* / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D011239:Prednisolone / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D005938:Glucocorticoids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011239:Prednisolone; D006072:Gossypol; C028178:gossypol acetic acid; D020123:Sirolimus
Acute lymphoblastic leukaemia; Gossypol and AT-101; MLL translocation; Prednisolone sensitivity