title: Preclinical activity of the novel B-cell-specific Moloney murine leukemia virus integration site 1 inhibitor PTC-209 in acute myeloid leukemia: Implications for leukemia therapy.
abstract: Curing patients with acute myeloid leukemia (AML) remains a therapeutic challenge. The polycomb complex protein B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of leukemia stem cells. We investigated the prognostic significance of BMI-1 in AML and the effects of a novel small molecule selective inhibitor of BMI-1, PTC-209. BMI-1 protein expression was determined in 511 newly diagnosed AML patients together with 207 other proteins using reverse-phase protein array technology. Patients with unfavorable cytogenetics according to Southwest Oncology Group criteria had higher levels of BMI-1 compared to those with favorable (P = 0.0006) or intermediate cytogenetics (P = 0.0061), and patients with higher levels of BMI-1 had worse overall survival (55.3 weeks vs. 42.8 weeks, P = 0.046). Treatment with PTC-209 reduced protein level of BMI-1 and its downstream target mono-ubiquitinated histone H2A and triggered several molecular events consistent with the induction of apoptosis, this is, loss of mitochondrial membrane potential, caspase-3 cleavage, BAX activation, and phosphatidylserine externalization. PTC-209 induced apoptosis in patient-derived CD34(+)CD38(low/-) AML cells and, less prominently, in CD34(-) differentiated AML cells. BMI-1 reduction by PTC-209 directly correlated with apoptosis induction in CD34(+) primary AML cells (r = 0.71, P = 0.022). However, basal BMI-1 expression was not a determinant of AML sensitivity. BMI-1 inhibition, which targets a primitive AML cell population, might offer a novel therapeutic strategy for AML.
authors.affiliation: Division of Medicine, Department of Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Division of Medicine, Department of Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chachad
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jo
authors.initials: J
authors.lastname: Ishizawa
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Division of Medicine, Department of Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Division of Medicine, Department of Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan.|Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000096:biosynthesis*; D011379:Prognosis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D006574:Heterocyclic Compounds, 2-Ring; C586999:PTC-209; D034741:RNA, Small Interfering; D013844:Thiazoles; D063150:Polycomb Repressive Complex 1
keywords: Acute myeloid leukemia; BMI-1; apoptosis; leukemia stem cell; prognosis