Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers

Abstract

Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.

Region-Specific Methylation Profiling in Acute Myeloid Leukemia

“…HTRA4 was detect as extremely high up methylated in TSS as well as in gene body regions. It is confirmed to be tumor suppressor gene and consider as biomarker in other cancers [ 34 ]. It was also described as down regulated in AML.…”

Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

“…SMAC mimetics represent a group of engineered analogues of SMAC for pharmacological use that work in a similar manner to native SMAC, inducing cell death. Preclinical studies have shown that SMAC mimetics induce cell death in a large proportion of primary AML samples: 51% of cases are clearly sensitive; 21% are moderately sensitive and 28% are resistant [310]. Interestingly, most of AML samples resistant to Ara-C, are sensitive to the SMAC mimetic BV6 [310].…”

“…Preclinical studies have shown that SMAC mimetics induce cell death in a large proportion of primary AML samples: 51% of cases are clearly sensitive; 21% are moderately sensitive and 28% are resistant [310]. Interestingly, most of AML samples resistant to Ara-C, are sensitive to the SMAC mimetic BV6 [310]. Sensitivity of AML blasts to SMAC mimetic correlated with low XIAP expression and presence of NPM1 mutations [310].…”

“…Interestingly, most of AML samples resistant to Ara-C, are sensitive to the SMAC mimetic BV6 [310]. Sensitivity of AML blasts to SMAC mimetic correlated with low XIAP expression and presence of NPM1 mutations [310]. Interestingly, the study of the mechanisms responsible for the induction of cell death in leukemic cells showed that AML blasts resistant to apoptosis are induced to cell death by induction of necroptosis via RIP1, RIP3 and MLKL activation [311].…”

Targeting RIPK1 in AML cells carrying FLT3‐ITD

“…Moreover, several studies reported an overexpression of IAP proteins in AML cells which is associated with poor prognosis . Furthermore, a number of recent reports pointed out the importance of using SMAC mimetics in AML cells to promote induction of cell death pathways …”