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. 2011 Jan 20;117(3):780-7.
doi: 10.1182/blood-2010-04-280503. Epub 2010 Nov 1.

Expression of ARC (apoptosis repressor with caspase recruitment domain), an antiapoptotic protein, is strongly prognostic in AML

Bing Z Carter  1 , Yi Hua Qiu, Nianxiang Zhang, Kevin R Coombes, Duncan H Mak, Deborah A Thomas, Farhad Ravandi, Hagop M Kantarjian, Erich Koller, Michael Andreeff, Steven M Kornblau
Affiliations

Expression of ARC (apoptosis repressor with caspase recruitment domain), an antiapoptotic protein, is strongly prognostic in AML

Bing Z Carter et al. Blood. .

Abstract

Regulators of apoptosis in acute myeloid leukemia (AML) have been extensively studied and are considered excellent therapeutic targets. Apoptosis repressor with caspase recruitment domain (ARC), an antiapoptotic protein originally found to be involved in apoptosis of cardiac cells, was recently demonstrated to be overexpressed in several solid tumors. To assess its importance in AML, we profiled ARC expression in 511 newly diagnosed AML patients using a validated robust reverse-phase protein array and correlated ARC levels with clinical outcomes. ARC was variably expressed in samples from patients with AML. ARC level was not associated with cytogenetic groups or with FLT-3 mutation status. However, patients with low or medium ARC protein levels had significantly better outcomes than those with high ARC levels: longer overall survival (median, 53.9 or 61.6 vs 38.9 weeks, P = .0015) and longer remission duration (median, 97.6 or 44.7 vs 31.1 weeks, P = .0007). Multivariate analysis indicated that ARC was a statistically significant independent predictor of survival in AML (P = .00013). Inhibition of ARC promoted apoptosis and sensitized cytosine arabinoside-induced apoptosis in OCI-AML3 cells. These results suggest that ARC expression levels are highly prognostic in AML and that ARC is a potential therapeutic target in AML.

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Figures

Figure 1
Figure 1
Comparison of ARC levels in paired newly diagnosed and relapse samples.
Figure 2
Figure 2
ARC expression and clinical characteristics of AML samples. (A) ARC level and FAB types of AML and APL patients (P < .0001). (B) ARC level and cytogenetic groups (P = .11). (C) ARC level and FLT-3 mutation status: ITD (left, P = .75) and D835 (right, P = .48). (D) ARC level and NPM1 mutation status.
Figure 3
Figure 3
ARC expression and blast counts of AML samples. (A) ARC level and PB blast count (P < .0001). (B) ARC level and BM blast count (P = .0608).
Figure 4
Figure 4
ARC expression and response of AML patients. (A) ARC level and treatment response (P = .0002). (B) ARC level and vital status (P = .0003).
Figure 5
Figure 5
ARC expression and clinical outcome of AML patients. (A) ARC level and overall survival (P = .0015). (B) ARC level and remission duration (P = .0007).
Figure 6
Figure 6
Inhibition of ARC promotes apoptosis and sensitizes Ara-C-induced cell death in AML cells. (A) OCI-AML3 cells were treated with ARC ASO by electroporation for 72 hours. ARC protein levels were determined at 48 hours by Western blot analysis. (B) OCI-AML3 cells were treated with ARC ASO (1 μg/million cells) for 24 hours, then with Ara-C for an additional 48 hours. Cell death was determined by annexin V (AnnV) staining in the presence of 7-amino-actinomycin D (7AAD).
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References

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