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CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia.

Astori A, Fredly H, Aloysius TA, Bullinger L, Mansat-De Mas V, de la Grange P, Delhommeau F, Hagen KM, Récher C, Dusanter-Fourt I, Knappskog S, Lillehaug JR, Pendino F, Bruserud Ø - Oncotarget (2013)

Bottom Line: Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML.This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML.The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1016, Institut Cochin, F-75014, Paris, France.

ABSTRACT
The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.

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High RINF mRNA expression is associated with decreased overall survival in AML; an analysis of three different patient populationsThe Kaplan-Meier curves (for survival analysis) and the log-rank test were performed by using the statistical SPSS 19.0. P values (log-rank test) of the comparison of the various groups of patients are indicated in each of the figures. (LEFT) The figure shows the results for the 27 unselected patients with newly diagnosed AML (Norwegian cohort) who received intensive chemotherapy. The figure compares the survival for the 9 patients with the highest RINF levels with the 18 patients with intermediate and low expression. The survival differed significantly between the two groups (p=0.012). (MIDDLE) The microarray dataset (Affymetrix GeneChip Human Genome HG-U133B) performed by Metzeler KH et al. [6] (163 patients) was downloaded from the Gene Expression Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE12417. The whole raw data were normalized using RMA (Robust Multiarray Averaging method) with the Expression Console software from Affymetrix. Since there were 3 probesets targeting CXXC5 (222996_s_at, 224516_s_at and 233955_x_at), the number of variable was reduced by PCA reduction analysis to determine the CXXC5 mRNA expression. The patients have been classified in 3 equivalent groups according to a high (n=55), an intermediate (n=54), or a low (n=54) RINF expression level. Here, the low (n=54) and intermediate (n=54) groups have been fused because they had similar survival. Note that because of an odd number of patients (n=163) the groups included different numbers of patients (55 versus 54). (RIGHT) RINF expression and survival was compared for 87 patients with core-binding factor AML; this analysis was also based on public microarray data [7] and again we observed a significant association between overall survival and RINF mRNA expression
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Figure 2: High RINF mRNA expression is associated with decreased overall survival in AML; an analysis of three different patient populationsThe Kaplan-Meier curves (for survival analysis) and the log-rank test were performed by using the statistical SPSS 19.0. P values (log-rank test) of the comparison of the various groups of patients are indicated in each of the figures. (LEFT) The figure shows the results for the 27 unselected patients with newly diagnosed AML (Norwegian cohort) who received intensive chemotherapy. The figure compares the survival for the 9 patients with the highest RINF levels with the 18 patients with intermediate and low expression. The survival differed significantly between the two groups (p=0.012). (MIDDLE) The microarray dataset (Affymetrix GeneChip Human Genome HG-U133B) performed by Metzeler KH et al. [6] (163 patients) was downloaded from the Gene Expression Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE12417. The whole raw data were normalized using RMA (Robust Multiarray Averaging method) with the Expression Console software from Affymetrix. Since there were 3 probesets targeting CXXC5 (222996_s_at, 224516_s_at and 233955_x_at), the number of variable was reduced by PCA reduction analysis to determine the CXXC5 mRNA expression. The patients have been classified in 3 equivalent groups according to a high (n=55), an intermediate (n=54), or a low (n=54) RINF expression level. Here, the low (n=54) and intermediate (n=54) groups have been fused because they had similar survival. Note that because of an odd number of patients (n=163) the groups included different numbers of patients (55 versus 54). (RIGHT) RINF expression and survival was compared for 87 patients with core-binding factor AML; this analysis was also based on public microarray data [7] and again we observed a significant association between overall survival and RINF mRNA expression

Mentions: We investigated a cohort of consecutive Norwegian patients including relapse patients (Table 1); the median age was relatively high (64 years) (Table 1) and several patients were therefore regarded as unfit for intensive chemotherapy. For these reasons, only 27 of these patients received intensive induction chemotherapy with cytarabine plus an anthracycline followed by 3 or 4 consolidation cycles with intensive chemotherapy for newly diagnosed leukemia (Fig. 2; Supplementary Fig. 1 and Supplementary Table 1). The 9 patients with the highest RINF expression in the AML cells then showed a significantly decreased overall survival compared with the groups with intermediate or low RINF levels (p=0.012). A significant association between overall survival after chemotherapy and RINF expression in the marrow-derived AML cells was also observed for the 20 French patients (Supplementary Fig. 2 and Supplementary Table 2; p=0.037).


CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia.

Astori A, Fredly H, Aloysius TA, Bullinger L, Mansat-De Mas V, de la Grange P, Delhommeau F, Hagen KM, Récher C, Dusanter-Fourt I, Knappskog S, Lillehaug JR, Pendino F, Bruserud Ø - Oncotarget (2013)

High RINF mRNA expression is associated with decreased overall survival in AML; an analysis of three different patient populationsThe Kaplan-Meier curves (for survival analysis) and the log-rank test were performed by using the statistical SPSS 19.0. P values (log-rank test) of the comparison of the various groups of patients are indicated in each of the figures. (LEFT) The figure shows the results for the 27 unselected patients with newly diagnosed AML (Norwegian cohort) who received intensive chemotherapy. The figure compares the survival for the 9 patients with the highest RINF levels with the 18 patients with intermediate and low expression. The survival differed significantly between the two groups (p=0.012). (MIDDLE) The microarray dataset (Affymetrix GeneChip Human Genome HG-U133B) performed by Metzeler KH et al. [6] (163 patients) was downloaded from the Gene Expression Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE12417. The whole raw data were normalized using RMA (Robust Multiarray Averaging method) with the Expression Console software from Affymetrix. Since there were 3 probesets targeting CXXC5 (222996_s_at, 224516_s_at and 233955_x_at), the number of variable was reduced by PCA reduction analysis to determine the CXXC5 mRNA expression. The patients have been classified in 3 equivalent groups according to a high (n=55), an intermediate (n=54), or a low (n=54) RINF expression level. Here, the low (n=54) and intermediate (n=54) groups have been fused because they had similar survival. Note that because of an odd number of patients (n=163) the groups included different numbers of patients (55 versus 54). (RIGHT) RINF expression and survival was compared for 87 patients with core-binding factor AML; this analysis was also based on public microarray data [7] and again we observed a significant association between overall survival and RINF mRNA expression
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3824541&req=5

Figure 2: High RINF mRNA expression is associated with decreased overall survival in AML; an analysis of three different patient populationsThe Kaplan-Meier curves (for survival analysis) and the log-rank test were performed by using the statistical SPSS 19.0. P values (log-rank test) of the comparison of the various groups of patients are indicated in each of the figures. (LEFT) The figure shows the results for the 27 unselected patients with newly diagnosed AML (Norwegian cohort) who received intensive chemotherapy. The figure compares the survival for the 9 patients with the highest RINF levels with the 18 patients with intermediate and low expression. The survival differed significantly between the two groups (p=0.012). (MIDDLE) The microarray dataset (Affymetrix GeneChip Human Genome HG-U133B) performed by Metzeler KH et al. [6] (163 patients) was downloaded from the Gene Expression Omnibus website (http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE12417. The whole raw data were normalized using RMA (Robust Multiarray Averaging method) with the Expression Console software from Affymetrix. Since there were 3 probesets targeting CXXC5 (222996_s_at, 224516_s_at and 233955_x_at), the number of variable was reduced by PCA reduction analysis to determine the CXXC5 mRNA expression. The patients have been classified in 3 equivalent groups according to a high (n=55), an intermediate (n=54), or a low (n=54) RINF expression level. Here, the low (n=54) and intermediate (n=54) groups have been fused because they had similar survival. Note that because of an odd number of patients (n=163) the groups included different numbers of patients (55 versus 54). (RIGHT) RINF expression and survival was compared for 87 patients with core-binding factor AML; this analysis was also based on public microarray data [7] and again we observed a significant association between overall survival and RINF mRNA expression
Mentions: We investigated a cohort of consecutive Norwegian patients including relapse patients (Table 1); the median age was relatively high (64 years) (Table 1) and several patients were therefore regarded as unfit for intensive chemotherapy. For these reasons, only 27 of these patients received intensive induction chemotherapy with cytarabine plus an anthracycline followed by 3 or 4 consolidation cycles with intensive chemotherapy for newly diagnosed leukemia (Fig. 2; Supplementary Fig. 1 and Supplementary Table 1). The 9 patients with the highest RINF expression in the AML cells then showed a significantly decreased overall survival compared with the groups with intermediate or low RINF levels (p=0.012). A significant association between overall survival after chemotherapy and RINF expression in the marrow-derived AML cells was also observed for the 20 French patients (Supplementary Fig. 2 and Supplementary Table 2; p=0.037).

Bottom Line: Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML.This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML.The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1016, Institut Cochin, F-75014, Paris, France.

ABSTRACT
The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.

Show MeSH
Related in: MedlinePlus