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

Yuki Nishida, Aya Maeda, Dhruv Chachad, Jo Ishizawa, Yi Hua Qiu, Steven M. Kornblau, Shinya Kimura, Michael Andreeff, Kensuke Kojima

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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+CD38low/- 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.

Original languageEnglish
Pages (from-to)1705-1713
Number of pages9
JournalCancer Science
Volume106
Issue number12
DOIs
StatePublished - 1 Dec 2015
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • BMI-1
  • Leukemia stem cell
  • Prognosis

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