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+ 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.

BMI1 Inhibitors Down-regulate NOTCH Signaling and Suppress Proliferation of Acute Leukemia Cells

“…Considering that BMI inhibitors did not significantly affect the viability of normal lymphocytes, our data indicate that they could be candidates for novel molecular targeting drugs against leukemia. Because BMI1 regulates cell stemness (5,6), BMI inhibitors could be used as drugs targeting leukemia stem cells. However, more research should be conducted to clarify molecular pathways targeted by BMI inhibitors and ensure their safety for normal hematopoietic stem cells.…”

“…B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a key regulatory component of PRC1 (4) known to promote cell proliferation by inhibiting expression of various genes such as cyclin-dependent kinase inhibitor 2A (CDKN2A) which encodes CDK inhibitor p16 INK4A and tumour suppressor p14 ARF . BMI1 was shown to be upregulated in several cancers, including acute leukemia (4)(5)(6), and a novel small molecule inhibitor of BMI1, PTC-209, has demonstrated inhibitory activity in human colorectal cancer (7), acute leukemia (6), and myeloma (8).…”

Knockdown of Sall4 inhibits intrahepatic cholangiocarcinoma cell migration and invasion in ICC-9810 cells

“…Bmi-1 gene was initially isolated as an oncogene in a retroviral-induced B- and T-cell leukemia, and it plays an essential role in leukemia stem cells 19,20. Bmi-1 deletion can inhibit tumor stem cell self-renewal and prevent leukemic recurrence 21. In addition, overexpression of Bmi-1 was found in many cancers and was used as an important marker for predicting the progression to acute myeloid leukemia,22 consistent with our recent findings in ICC.…”

The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells

“…19 In mouse models with patient-derived colorectal cancer, PTC-209 potently suppressed tumor growth and eradicated cancer-initiating cells. 21 We reported that PTC-209 induces apoptosis in AML patient-derived CD34 + CD38 low/− stem/progenitor cells.…”