title: The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells.
abstract: Disease recurrence is the major problem in the treatment of acute myeloid leukemia (AML). Relapse is driven by leukemia stem cells, a chemoresistant subpopulation capable of re-establishing disease. Patients with p53 mutant AML are at an extremely high risk of relapse. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is required for the self-renewal and maintenance of AML stem cells. Here we studied the effects of a novel small molecule inhibitor of BMI-1, PTC596, in AML cells. Treatment with PTC596 reduced MCL-1 expression and triggered several molecular events consistent with induction of mitochondrial apoptosis: loss of mitochondrial membrane potential, BAX conformational change, caspase-3 cleavage and phosphatidylserine externalization. PTC596 induced apoptosis in a p53-independent manner. PTC596 induced apoptosis along with the reduction of MCL-1 and phosphorylated AKT in patient-derived CD34+CD38low/-stem/progenitor cells. Mouse xenograft models demonstrated in vivo anti-leukemia activity of PTC596, which inhibited leukemia cell growth in vivo while sparing normal hematopoietic cells. Our results indicate that PTC596 deserves further evaluation in clinical trials for refractory or relapsed AML patients, especially for those with unfavorable complex karyotype or therapy-related AML that are frequently associated with p53 mutations.
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Maeda
authors.affiliation: PTC Therapeutics, South Plainfield, NJ, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: PTC Therapeutics, South Plainfield, NJ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
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, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: AlRawi
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsue
authors.affiliation: PTC Therapeutics, South Plainfield, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Weetall
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dumble
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: PMV Pharmaceuticals Inc., Cranbury, NJ, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Davis
authors.affiliation: PTC Therapeutics, South Plainfield, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Branstrom
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kojima
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C489421:Bmi1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1