title: BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts.
abstract: FLT3 defines a promising target for the treatment of acute myeloid leukemia (AML). In contrast to their efficacy in cell lines, FLT3-specific inhibitors as single agents have only modest clinical activity in patients with AML. As demonstrated here, overexpression of anti-apoptotic proteins of the BCL2 family leads to resistance against FLT3 inhibitors in a hematopoietic cell line model with activating FLT3 mutations. The susceptibility to FLT3 inhibition could be restored by treatment with the novel BH3 mimetic ABT-737. Primary AML samples tested in our study showed a high expression of BCL2 protein, but not of BCL-xL or MCL1. BCL2 protein levels were not reduced after dephosphorylation of FLT3 and its downstream target STAT5 in patient samples with FLT3 internal tandem duplications. Interestingly, treatment with ABT-737 caused apoptotic cell death in all primary AML samples at submicromolar level and synergized efficiently with FLT3 inhibition in AML samples with activating FLT3 mutations. In contrast to AML cell lines, BCR-ABL transformed human cells showed resistance to ABT-737, which might be due to the induction of MCL1 by BCR-ABL. Inhibition of BCL2 family members might define a novel highly efficient and specific strategy in the combined or monotreatment of AML.
authors.affiliation: Clinical Cooperative Group Leukemia, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, GSF-National Research Center for Environment and Health, Munich, Germany. tobias.kohl@gsf.de
authors.forename: T M
authors.initials: TM
authors.lastname: Kohl
authors.forename: C
authors.initials: C
authors.lastname: Hellinger
authors.forename: F
authors.initials: F
authors.lastname: Ahmed
authors.forename: C
authors.initials: C
authors.lastname: Buske
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.forename: S K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: K
authors.initials: K
authors.lastname: Spiekermann
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology; D008875:Middle Aged; D018716:Molecular Mimicry; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators; D051020:bcl-X Protein / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; C494811:BCL2L1 protein, human; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; D015534:Trans-Activators; D051020:bcl-X Protein; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3