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The Homeobox Gene CDX2 Is Aberrantly Expressed and Associated with an Inferior Prognosis in Patients with Acute Lymphoblastic Leukemia

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The Homeobox Gene CDX2 Is Aberrantly Expressed and Associated with an Inferior Prognosis in Patients with Acute Lymphoblastic Leukemia Leukemia (2009) 23, 649–655 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu ORIGINAL ARTICLE The homeobox gene CDX2 is aberrantly expressed and associated with an inferior prognosis in patients with acute lymphoblastic leukemia S Thoene1,2,4, VPS Rawat1,2,4, B Heilmeier1, E Hoster1, KH Metzeler1, T Herold1, W Hiddemann1,2,NGo¨kbuget3, D Hoelzer3, SK Bohlander1,2, M Feuring-Buske1,2 and C Buske1,2 1Department of Medicine III, Klinikum Grosshadern, Munich, Germany; 2Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany and 3Department of Medicine III, Johann Wolfgang Goethe University, Frankfurt/Main, Germany Molecular characterization of acute lymphoblastic leukemia gene deregulation.11 However, it was shown that besides Hox (ALL) has greatly improved the ability to categorize and genes Cdx2 regulates other stem cell regulatory genes, such as Scl, prognostify patients with this disease. In this study, we show 12 that the proto-oncogene CDX2 is aberrantly expressed in the Gata1 and Runx1. Thus, aberrant expression of CDX2 might majority of cases with B-lineage ALL and T-ALL. High expres- perturb the stem cell regulatory network at different levels. sion of CDX2 correlated significantly with the ALL subtype We now report that CDX2 is aberrantly expressed in 81% of pro-B ALL, cALL, Ph þ ALL and early T-ALL. Furthermore, high adult patients with ALL, and that high expression levels of this expression of CDX2 was associated with inferior overall proto-oncogene predict poor treatment outcome in patients with survival and showed up as a novel and strong risk factor for this disease. ALL in bivariate analysis. Functional analyses showed that overexpression of Cdx2 in murine bone marrow progenitors perturbed genes involved in lymphoid development and that depletion of CDX2 in the human ALL cell line Nalm6 inhibited Materials and methods colony formation. These data indicate that aberrant CDX2 expression occurs frequently and has prognostic impact in Patient samples adult patients with ALL. Bone marrow or peripheral blood samples from 57 newly Leukemia (2009) 23, 649–655; doi:10.1038/leu.2008.355; diagnosed adult patients with ALL were analyzed. Of these, 31 published online 22 January 2009 patients were enrolled between 2000 and 2004 in the protocols Keywords: CDX2; acute lymphoblastic leukemia; HOX genes; prognostic factor 06/99 and 07/03 of the German Multicenter Study Group for Adult ALL (GMALL).13 Sixteen patients were enrolled in other multi- center protocols (GMALL Elderly 12/96, GMALL Elderly 01/03 Introduction and GMALL B-ALL/NHL 02). Ten patients were treated outside a study protocol. Patients gave written informed consent according With intensive risk adapted chemotherapy, stem cell transplanta- to the Declaration of Helsinki. The studies were approved by the tion and targeted therapies, the outcome of adult acute ethics board of the University Frankfurt am Main, Germany. lymphoblastic leukemia (ALL) has improved in the past decades from o10 to 40–50%.1,2 In addition, great progress has been made in understanding the biology of ALL: recently, genome-wide Quantitative PCR analyses of ALL patients showed deletions and mutations of genes Expression analyses were performed by TaqMan qRT-PCR associated with lymphoid development, such as LEF1, TCF, PAX5, using the Applied Biosystems 7900HT fast real-time PCR IKAROS and NOTCH1.3–5 However, for the majority of ALL cases system with pre-designed gene expression assays purchased the molecular mechanisms driving the malignant transformation from Applied Biosystems (Assay IDs CDX2: Hs01078080_m1, are unknown. Recently, data from experimental models and gene HOXA7: Hs00600844_m1, HOXA9: Hs00365956_m1, expression profiling in patients with acute myeloid leukemia HOXB6: Hs00980016_m1, TATA box binding protein (TBP): (AML) have identified CDX2 as a powerful oncogene when 4333769F; Applied Biosystems, Foster City, CA, USA). Reac- aberrantly expressed in adult hematopoietic progenitor cells:6–8 tions were run with 1 ml of cDNA containing the equivalent of the ‘caudal related homeobox gene’ CDX2 belongs to the family 50 ng total RNA in a total volume of 20 ml. DCT values were ofso-called‘ParaHoxgenes’,whichalsoincludesCDX1, CDX4 obtained by normalization to the housekeeping gene TBP. For and the GSH2 homeobox gene.9 Normally expression of CDX2 is patients with undetectable DCT values (negative samples), the tightly regulated in the adult organism, with expression in the lowest possible DCT was calculated by subtracting the CT value intestine but no expression in adult hematopoietic tissue.10 It was of TBP from the maximum number of cycles (45 cycles). Note shown that CDX2 is among the most frequent aberrantly expressed that DCT values are inversely correlated to gene expression proto-oncogenes in AML, with up to 89% of AML cases with levels. For the ‘low density assay’ (custom design LDA, array normal karyotype expressing CDX2.8,11 In AML patients, high configuration 7), 92 different genes involved in self-renewal, expression levels of CDX2 were closely associated with HOX proliferation and differentiation were selected. Each sample was run in duplicate and fold expression was calculated using the DDC method after normalizing to b-actin. Correspondence: Dr C Buske, Department of Medicine III, Klinikum T Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany. E-mail: [email protected] 4These authors contributed equally to this work. Retroviral infection and in vitro assays 7 Received 3 November 2008; accepted 19 November 2008; published Primary mouse BM cells were transduced as described earlier. online 22 January 2009 For transduction of Cdx2, cells were co-cultured with irradiated CDX2 in acute lymphoblastic leukemia S Thoene et al 650 (4000 cGy from a 137Cs g-radiation) GP þ E86 Cdx2 producer SCIENCE/hannon.html. Four different shRNAs were obtained cells. Clonogenicity of short hairpin RNA (shRNA) transduced and cloned into the MSCV/LTRmiR30-PIG retroviral vector Nalm6 cells was analyzed in the CFC assay as described earlier (kindly provided by Scott W Lowe, Howard Hughes Medical (Methocult H4434, Stemcell Technologies, Vancouver, British Institute, New York, USA). Short hairpin RNA sequences are Colombia, Canada).14 available on request. Cell lines were retrovirally transduced as described earlier in Ahmed et al.14 Short hairpin RNA Methylation analysis Short hairpin RNA against CDX2 (NM_001265) were designed Quantitative DNA methylation status of the CpG island surround- using the following website http://www.cshl.org/public/ ing the transcription start site of CDX2 (À181 to þ 163)15 was 20.00 20.00 15.00 15.00 10.00 10.00 T T C C ∆ ∆ 5.00 5.00 0.00 0.00 (Normalized to TBP) (Normalized to TBP) -5.00 -5.00 Pro-B B-ALL + Early Thymic c-ALL Ph+ ALL Total Total ALL Burkitt T-ALL T-ALL ALL AML % Positive patients 100 40 71 70 100 100 81 79 No of patients positive/ total (9/9) (4/10) (5/7) (7/10) (10/10) (11/11) (4657) (91/115) 12 10 8 Low/ absent CDX2 expression 6 High CDX2 expression 4 Number of cases 2 0 c-ALL Ph+ Pro-B B-ALL/ Early Thymic ALL ALL Burkitt T-ALL T-ALL 16.00 14.00 12.00 CDX2 10.00 HOXA7 8.00 T 6.00 HOXA9 C ∆ 4.00 HOXB6 2.00 0.00 (Normalized to TBP) -2.00 -4.00 -6.00 CD34+ MNC c-ALL Thymic Ph+ ALL Early Pro-B B-ALL/ (n=3) (n=3) (n=6) T-ALL (n=6) T-ALL ALL Burkitt (n=5) (n=4) (n=6) (n=3) Figure 1 Quantitative expression of CDX2 and HOX genes in ALL patients. (a) Expression analysis of CDX2 in different acute lymphoblastic leukemia (ALL) subtypes and acute myeloid leukemia (AML) with normal and abnormal karyotype was performed by qRT-PCR. DCT values were calculated by normalization to the housekeeping gene TATA box binding protein (TBP). Dots represent individual patients, bars indicate the median expression level of CDX2 in the different ALL subgroups (±0.5 Â interquartile range (IQR)). The dashed line indicates the median expression level of CDX2 for all patients measured. Note that DCT values are inversely correlated to expression level. (b) Distribution of patients with low/absent versus high CDX2 expression levels in different ALL subgroups. Patients with no CDX2 expression or expression above the median (DCT of 7.14) were considered as low/absent, patients with CDX2 expression equal to or below the median as high. (c) Expression of HOX genes in CDX2-positive ALL patients and normal healthy individuals. (MNC, mononuclear BM cells, CD34 þ , CD34 þ BM cells) quantified by qRT-PCR. Columns represent average expression levels±s.e.m. The number of patient samples is indicated. Leukemia CDX2 in acute lymphoblastic leukemia S Thoene et al 651 assessed by pyrosequencing of bisulfite-treated genomic varied substantially between different ALL subgroups: the DNA. After bisulfite treatment of genomic DNA, the region median expression level was 16-fold higher in pro-B ALL of interest was amplified by the primer set CDX2_F (50-TTGGT compared with mature B-ALL and 29-fold higher in early T-ALL GTTTGTGTTATTATTAATAGAGTTTTGTAAATAT-30)andCDX2_R compared with thymic T-ALL (Figure 1a, Table 1). When high (50-biotin-ATCCCAAAACAAACCTCACCATACTA-30). PCR pro- and low CDX2 expression levels were defined as below or duct was immobilized to Streptavidin Sepharose HP beads (GE above the median DCT value, none of the patients with mature Healthcare, Waukesha, WI, USA) followed by annealing to the B-ALL or thymic T-ALL had high CDX2 expression, whereas all sequencing primer. For sequencing three different primers were the patients with pro-B ALL, 8 of 10 patients with cALL and 8 of used, which are available on request. CpG analysis was done 11 patients with Ph þ ALL (10 pre-B/c-ALL and 1 pro-B ALL) with Pyro Q-CpG software (Biotage, Uppsala, Sweden).
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