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

Cancer Science

Yuki Nishida¹  Aya Maeda¹  Dhruv Chachad²  Jo Ishizawa²  Yi Hua Qiu²  Steven M. Kornblau²  Shinya Kimura¹  Michael Andreeff² 

[1] 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

关键词: Acute myeloid leukemia;    apoptosis;    BMI‐1;    leukemia stem cell;    prognosis;   

DOI  :  10.1111/cas.12833

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.