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: Yuki Nishida, Aya Maeda, Dhruv Chachad, Jo Ishizawa, Yi Hua Qiu, Steven M Kornblau, Shinya Kimura, Michael Andreeff, Kensuke Kojima
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 12 Pg. 1705-13 (Dec 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 26450753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• BMI1 protein, human
• Heterocyclic Compounds, 2-Ring
• PTC-209
• RNA, Small Interfering
• Thiazoles
• Polycomb Repressive Complex 1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Flow Cytometry
• Heterocyclic Compounds, 2-Ring (pharmacology)
• Humans
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (mortality, pathology)
• Polycomb Repressive Complex 1 (biosynthesis)
• Prognosis
• RNA, Small Interfering
• Real-Time Polymerase Chain Reaction
• Thiazoles (pharmacology)
• Transfection