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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

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 significanc...

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Detalles Bibliográficos
Autores principales: Nishida, Yuki, Maeda, Aya, Chachad, Dhruv, Ishizawa, Jo, Qiu, Yi Hua, Kornblau, Steven M., Kimura, Shinya, Andreeff, Michael, Kojima, Kensuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714665/
https://www.ncbi.nlm.nih.gov/pubmed/26450753
http://dx.doi.org/10.1111/cas.12833
Descripción
Sumario: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.