Deregulated apoptosis signaling in core-binding factor leukemia differentiates clinically relevant, molecular marker-independent subgroups

Abstract

Core-binding factor (CBF) leukemias, characterized by translocations t(8;21) or inv(16)/t(16;16) targeting the CBF, constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, about 40% of patients relapse and the current classification system does not fully reflect this clinical heterogeneity. Previously, gene expression profiling (GEP) revealed two distinct CBF leukemia subgroups displaying significant outcome differences and identified apoptotic signaling, MAPKinase signaling and chemotherapy-resistance mechanisms among the most significant differentially regulated pathways. We now tested different inhibitors of the respective pathways in a cell line model (six cell lines reflecting the CBF subgroup-specific gene expression alterations), and found apoptotic signaling to be differentiating between the CBF subgroup models. In accordance, primary samples from newly diagnosed CBF AML patients (n ¼ 23) also showed differential sensitivity to in vitro treatment with a Smac mimetic such as BV6, an antagonist of inhibitor of apoptosis (IAP) proteins, and ABT-737, a BCL2 inhibitor. Furthermore, GEP revealed the BV6-resistant cases to resemble the previously identified unfavorable CBF subgroup. Thus, our current findings show deregulated IAP expression and apoptotic signaling to differentiate clinically relevant CBF subgroups, which were independent of known molecular markers, thereby providing a starting point for novel therapeutic approaches.

Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia

“…html) by applying the JustRMA (robust multi-array average) algorithm and previously reported filtering criteria (data are available at http://www.ncbi.nlm.nih.gov/projects/geo; GSE62533 in case of CLL and GSE46819 in case of CBF-AML). 25 BRB Array Tools Version 4.2.1 was also used for data analysis using class comparison and pathway class comparison tools as previously described. 26 All tests were two-sided.…”

“…25 Pairwise analysis comparing BV6-and DMSOtreated samples irrespective of the tumor entity resulted in 868 distinctly regulated genes by BV6 (i.e., 644 downregulated and 224 upregulated genes, Supporting Information Table 5), including among others TRAF1, TNFAIP3, TNFRSF4, NFKBIA, BIRC3 and SOD3. Importantly, using DAVID functional annotation clustering tool, we identified among 70 annotation clusters with enrichment scores > 1.0 the two clusters "regulation of programmed cell death" and "positive regulation of NF-jB transcription factor activity" in both the CLL as well as the CBF AML cohort (Supporting Information Table 6, Table 1B), indicating that BV6 alters these gene clusters independently of the tumor entity.…”

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

“…51 Importantly, deregulated IAP expression and apoptotic signaling were among the signaling pathways that were found to differentiate these two clinically relevant CBF subgroups. 50 Whereas there is no consensus on the prognostic value of XIAP in adult AML, XIAP has been associated with adverse prognosis in pediatric leukemia by independent studies. Accordingly, high XIAP expression was identified as an unfavorable prognostic factor in childhood de novo AML.…”

“…50 CBF leukemias are a subgroup of AML that are characterized by t(8;21) or inv(16)/t(16;16) translocations targeting the CBF, and are usually associated with a favorable prognosis. Gene expression profiling studies have previously identified two distinct CBF subgroups, independently of known molecular markers that exhibit significant differences in outcome.…”

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

“…51 For the comparison of scrambled versus Plcγ1 shRNA-treated cell lines, supervised analysis was carried out as previously reported (for Class Comparison Analysis the nominal significance level of each univariate test (two-sample t-test with random variance model) was Po0.05). 52 Results were visualized using TreeView Software (University of California, Berkeley, CA, USA; http://www.eisenlab.org/eisen/?page_id=42).…”