title: Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML.
abstract: Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic 'reader' BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34⁺/CD38⁻ and CD34⁺/CD38⁺ stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC₅₀ 0.05-0.5 µM) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38⁻ and CD34⁺/CD38⁺ stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34⁺/CD38⁻ and CD34⁺/CD38⁺ AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials.
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.forename: Junwei
authors.initials: J
authors.lastname: Shi
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Vakoc
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
chemical_list: D051997:ADP-ribosyl Cyclase 1; D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D003561:Cytarabine; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C498154:CD38 protein, human