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Clinical Cancer Research Vol. 12, 4845-4850, August 15, 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

CpG Island Methylator Phenotype Redefines the Prognostic Effect of t(12;21) in Childhood Acute Lymphoblastic Leukemia

Jose Roman-Gomez1, Antonio Jimenez-Velasco2, Xabier Agirre3, Juan A. Castillejo1, German Navarro2, Maria J. Calasanz3, Leire Garate3, Edurne San Jose-Eneriz3, Lucia Cordeu3, Felipe Prosper3, Anabel Heiniger2 and Antonio Torres1

Authors' Affiliations: 1 Hematology Department, Reina Sofia Hospital, Cordoba; 2 Hematology Department, Carlos Haya Hospital, Malaga; and 3 Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

Requests for reprints: Jose Roman-Gomez, Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n, 14004 Cordoba, Spain. Phone: 34-957-010250; Fax: 34-957-010429; E-mail: peperosa{at}teleline.es.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
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Purpose: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome.

Experimental Design: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples.

Results: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP– group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP– group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples.

Conclusion: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.

The t(12;21)(p13;q22) translocation, which involves the ETV6 gene (previously TEL) located on 12p13 and the RUNX1 gene (previously AML1) on 21q22, is found in 20% to 30% of children with B cell precursor acute lymphoblastic leukemia (BCP-ALL; ref. 1). In general, t(12;21)-positive BCP-ALL is associated with a favorable prognosis, although conflicting results have been described. Relapses have been reported in ~20% of cases, generally after a long remission period, although the relapse incidence varies and may depend on the treatment protocol (2–5). In a series of patients treated with the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocol between 1980 and 1991, none of the 22 patients with the ETV6/RUNX1 rearrangement relapsed (2). In the Berlin-Frankfurt-Munster clinical trials, however, 20% to 24% of patients with BCP-ALL studied during relapse had the ETV6/RUNX1 rearrangement, a frequency similar to that observed at diagnosis (3–5). Equally, there are isolated reports of event-free survivals measured in months only, or while patients were still on treatment (6, 7).

Because the t(12;21)-positive BCP-ALL group seems to be a heterogeneous group including patients that can be cured with conventional therapy and patients with dismal prognosis that need more intensive regimens, it would be beneficial to identify high-risk ETV6/RUNX1-positive patients at diagnosis or soon thereafter in order to modify their initial therapy with the goal of preventing treatment failure. However, conventionally applied epidemiologic features fail to identify these patients. There are no significant differences in event-free survival for t(12;21)-positive children based on age, presenting leukocyte blood cell count, or sex (8). Moreover, although t(12;21) is mostly associated with karyotypes characterized by modal numbers ranging from 45 to 52, trisomy 21, 12p aberrations, nonspecific chromosome deletions, deletion of the normal ETV6 allele, duplication of the fusion gene, and RUNX1 extra signal, these abnormalities secondary to the ETV6/RUNX1 do not seem to influence patient outcome (9). Therefore, useful molecular markers for risk-specific adjustments in therapeutic intensity are necessary in this disease.

DNA methylation is an essential mechanism for the regulation of gene expression in mammalian cells (10). Methylation occurs at cytosine residues within CpG dinucleotides and many genes are enriched with these dinucleotides in their promoters. These regions are known as CpG islands and are generally nonmethylated, a condition that allows genes to be transcriptionally competent. Methylation of CpG islands within gene promoters leads to transcriptional silencing through recruitment of methyl-CpG binding protein and histone deacetylases (11, 12). Hence, identification of the methylation patterns of CpG islands in mammalian cells is important for understanding normal and pathologic gene expression. Several reports have shown that abnormal methylation of CpG islands may contribute significantly to the pathogenesis of human leukemias providing an alternative route to gene mutation of cancer-related genes. We have recently shown that the methylation of cytosine nucleotides in ALL cells can help to inactivate tumor-suppressive apoptotic or growth-arresting responses and has a prognostic effect in B and T cell ALL (13, 14). The presence in individual tumors of multiple genes simultaneously methylated (a condition termed CpG island methylator phenotype or CIMP+) is an independent factor of poor prognosis in both childhood and adult ALL in terms of disease-free survival (DFS) and overall survival (OS). Moreover, methylation status was able to redefine the prognosis of selected ALL groups with well-established prognostic features. Lack of CIMP (CIMP–) improved the general poor outcome of patients presenting Philadelphia chromosome, high WBC count at diagnosis, or T cell phenotype (13, 14).

In order to determine whether methylation profile is also of clinical relevance in ETV6/RUNX1-positive ALL, we have examined multiple key cancer genes undergoing epigenetic inactivation in a set of de novo t(12;21)-positive BCP-ALLs of childhood with the aim of obtaining a map of this alteration in the disease and its possible correlation with clinical features and outcome of the patients.


   Materials and Methods
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Patients. We studied 54 consecutive children (32 male and 22 female) with de novo ETV6/RUNX1-positive BCP-ALL who were enrolled in a multicenter study of the PETHEMA Spanish Study Group. All these patients were referred to the Reina Sofia Hospital of Cordoba, Spain, from January 1993 to December 2004. The median age at diagnosis was 5 years (range, 2-14 years). The study was approved by the Investigational Review Boards in accordance with the policies of the Department of Health and Human Services. Informed consent was obtained from the patient's guardians. Diagnosis was established according to standard morphologic, cytochemical, and immunophenotypic criteria. After diagnosis, patients were entered in ALL protocols for standard risk patients of the PETHEMA Spanish study group. All these patients were included in the specific PETHEMA ALL-93 treatment protocol. The design and results of this protocol have been previously reported (15, 16). Fifteen patients relapsed, whereas six patients received stem cell transplantation (two autologous and four allogeneic) in the second complete remission (CR). There are 47 patients currently alive. The clinical characteristics of the patients are listed in Table 1 . Preliminary methylation data from 14 of these patients have been previously reported (13).


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  		Table 1. Clinical characteristics and outcome of 54 t(12;21)-positive BCP-ALL children according to gene methylation status

 
In addition, we also studied 190 consecutive ETV6/RUNX1-negative BCP-ALL children diagnosed during the same period of time in order to compare the methylation profiles of both ETV6/RUNX1-positive and -negative BCP-ALL.

Cytogenetic investigations. Chromosome banding analyses of bone marrow samples were done using standard methods. All patients in the study cohort were analyzed with fluorescence in situ hybridization or reverse-transcriptase PCR or both, using standard methods for the presence of the cryptic translocation ETV6/RUNX1.

Gene selection. Bone marrow specimens were obtained from all the patients at the moment of diagnosis. High-molecular weight DNA was prepared from mononuclear diagnostic marrow cells using conventional methods, frozen at –80°C, and retrospectively analyzed to assess the role of methylation profile. In all the cases, the diagnostic bone marrow sample contained blast cells in the ratio of at least 70%. We studied 38 genes belonging to all of the molecular pathways involved in cell immortalization and transformation: cell cycle (FHIT, LATS2, p15, p16, p57, REPRIMO, and RIZ), cell adherence and metastasis process (ADAMTS1, ADAMTS5, CDH1, and CDH13), p53 network (ASPP1, p14, and p73), apoptosis (APAF1, ARTS, DAPK, DBC1, DIABLO, and TMS1), inhibitors of the oncogenic WNT signaling pathway (DKK3, HDPR1, sFRP1, sFRP2, sFRP4, sFRP5, and WIF1), differentiation regulation (NES1), folate carrier (hRFC), hormone receptor superfamily (PGR), ubiquitination (PACRG and PARK2), DNA repair (SMC1L1 and SMC1L2), tyrosine kinase with an essential role in signal transduction (SYK), negative regulator of the Jak/STAT signaling pathway (SHP1), and main tumor-suppressor genes (LATS1 and PTEN; Table 2 ). Different criteria were used for gene selection. ADAMTS1, ADAMTS5, APAF1, ASPP1, CDH1, CDH13, DAPK, DIABLO, DKK3, HDPR1, LATS1, LATS2, NES1, PACRG, PARK2, PTEN, p14, p16, p15, p57, p73, sFRP1, sFRP2, sFRP4, sFRP5, SHP1, SYK, TMS1, and WIF1 were selected because of their frequent methylation in ALL (13, 14). The other genes were studied because they have been found to be methylated in other malignancies including leukemic cell lines, and their abnormal expression could have potentially important roles in ALL (17–24). The regions in which these genes reside are not prone to mutations, deletions, or rearrangement in the majority of human leukemias; however, microsatellite markers from these regions have shown that most of them are common sites for loss of heterozygosity in ALL (25). Each of these genes possesses a CpG island in the 5' region, which is normally unmethylated in corresponding normal tissues as expected for a typical CpG island. We and others have shown, in previous studies for such genes in individual tumor types, that when these CpG islands are hypermethylated in cancer cells, the expression of the corresponding gene is silenced and the silencing can be partially relieved by demethylation of the promoter region (13, 14, 17–24). For all these genes, we have analyzed, at least, 10 normal marrow and peripheral blood specimens, none of which showed methylation.


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  		Table 2. Genes studied for methylation in t(12;21)-positive BCP-ALL

 
Methylation-specific PCR. Aberrant promoter methylation of these genes was determined by a methylation-specific PCR (MSP) method after bisulfite treatment of DNA as reported by Herman et al. (26). The primer sequences of each gene for the unmethylated and methylated reactions have been reported elsewhere (13, 14, 17–24). "Hot start" PCR was done for 30 cycles consisting of denaturation at 95°C for 1 minute, annealing at 60°C for 1 minute, and extension at 72°C for 1 minute, followed by a final 7-minute extension for all primer sets. The products were separated by electrophoresis on 2% agarose gel. Bone marrow DNA from healthy donors was used as a negative control for methylation-specific assays. Human male genomic DNA universally methylated for all genes (Intergen Company, Purchase, NY) was used as a positive control for methylated alleles. Water blanks were included with each assay. The presence of a clearly visible band in the MSP using primers for the methylated alleles was considered as a positive result for methylation. This result was always confirmed by repeat MSP assays after an independently done bisulfite treatment. In the sporadic cases in which only faint bands were observed in both analyses, methylation results were validated by Southern blot and/or sequencing and/or association with lack of expression assessed by reverse-transcriptase PCR as appropriate.

Statistical analysis. Although there is, as yet, no consensus definition for CIMP+, patients with ETV6/RUNX1-positive BCP-ALL were arbitrarily classified into two different methylation groups: cases showing methylation at three or more loci were defined as CIMP+, whereas those in which methylation was low occurring at two or fewer loci were defined as CIMP–. P values for comparisons of continuous variables between groups of patients were two-tailed and based on the Wilcoxon rank sum test. P values for dichotomous variables were based on the Fisher exact test. The remaining P values were based on the Pearson {chi}2 test. OS was measured from the day of diagnosis until death from any cause and was censored only for patients known to be alive at last contact. DFS was measured from the day that CR was established until either relapse or death without relapse, and it was censored only for patients who were alive without evidence of relapse at the last follow-up. The distributions of OS and DFS curves were estimated by the method of Kaplan and Meier, with 95% confidence intervals calculated by means of Greenwood's formula. Comparisons of OS or DFS between groups were based on the log-rank test. Comparisons adjusted for significant prognostic factors were based on Cox regression models and hazard regression models. All relapse and survival data were updated on March 2005, and all follow-up data were censored at that point.


   Results
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Frequency of methylation in ETV6/RUNX1-positive BCP-ALL. Gene methylation frequencies varied from 2% to 58%. Twenty-three genes showed a relatively high frequency of aberrant methylation: NES1 (58%), ADAMTS1 (47%), PGR (45%), DKK3 (42%), sFRP1 (36%), CDH1 (36%), SMC1L2 (36%), ADAMTS5 (34%), CDH13 (33%), REPRIMO (33%), RIZ (31%), PARK2 (31%), PACRG (31%), P73 (30%), PTEN (29%), HDPR1 (28%), WIF1 (27%), LATS2 (27%), FHIT (21%), hRFC (21%), DIABLO (21%), sFRP2 (20%), and sFRP5 (20%). The other 15 genes studied showed a low frequency (2-18%) of methylation (Table 3 ). No methylated genes were found in 6 of 54 patients (11%), whereas most t(12;21)-positive BCP-ALLs (48 of 54, 89%) had methylation of at least one gene, ranging from 1 to 20 methylated genes. No case was found to have methylation of >20 genes. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP– group (0-2 methylated genes) and 34 (63%) in the CIMP+ group (>2 methylated genes).


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  		Table 3. Methylation profile in BCP-ALL

 
Comparative analysis of the methylation frequencies between children with ETV6/RUNX1-positive and ETV6/RUNX1-negative BCP-ALL classifies the 38 genes examined into three groups. The first group is that of genes showing significantly higher frequencies of methylation in ETV6/RUNX1-positive compared with ETV6/RUNX1-negative BCP-ALL (DKK3, sFRP2, PTEN, and P73; Table 3). The second group was that of genes showing significantly higher frequencies of methylation in ETV6/RUNX1-negative compared with ETV6/RUNX1-positive BCP-ALL (ARTS, hRFC, SMC1L2, sFRP4, SHP1, and LATS1), and the third group was that of genes demonstrating a similar frequency of methylation in both subtypes of BPC-ALL (the remaining 28 genes). Furthermore, although CIMP+ was equally distributed among ETV6/RUNX1-positive BCP-ALL (63%) and ETV6/RUNX1-negative BCP-ALL (65%), the density of gene methylation in ETV6/RUNX1-positive BCP-ALL (mean of methylated genes, 6.8 ± 0.8) was significantly higher compared with ETV6/RUNX1-negative BCP-ALL (mean of methylated genes, 4.8 ± 0.5; P = 0.008).

Clinical outcome of ETV6/RUNX1-positive BCP-ALL and methylation profile. As shown in Table 1, clinical and laboratory characteristics did not differ significantly between methylation groups. Table 1 also details the relapse history, CR rates and mortality for patients included in the different methylation groups. CR rates of patients in both CIMP– and CIMP+ groups were 100%. However, patients in the CIMP– group had a lower relapse rate than patients in the CIMP+ group (5% versus 44%, P = 0.003). Mortality rate was also lower for the CIMP– group compared with the CIMP+ group (0% versus 19%, P = 0.04).

We analyzed the DFS among patients who achieved CR according to the methylation profile. Estimated DFS rates at 9 years were 92% and 33% for CIMP– and CIMP+ groups, respectively (P = 0.002; Fig. 1A ). The actuarial OS at 9 years calculated for all leukemic patients was 100% for CIMP– patients and 73% for CIMP+ patients (P = 0.04; Fig. 1B).


Figure 1
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  		Fig. 1. Kaplan-Meier survivor function for ETV6/RUNX1-positive BCP-ALL patients. DFS (A) and OS (B) curves for all the patients enrolled in this study according to the methylation profile. CIMP– (patients with 0-2 methylated genes, n = 20); CIMP+ (patients with >2 methylated genes, n = 34). Log-rank test was significant for both DFS (P = 0.002) and OS (P = 0.04).

 
A multivariate analysis of potential prognostic factors showed that methylation profile was the only independent prognostic factor in predicting DFS (P = 0.01) and OS (P = 0.05; Table 4 ).


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  		Table 4. Multivariate Cox model for DFS and OS in t(9;22)-ALL

 

   Discussion
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Epigenetic gene silencing is increasingly being recognized as a common way in which cancer cells inactivate cancer-related genes (11, 12). In addition to its pathogenic implications, promoter hypermethylation and transcriptional repression of functionally important cancer-related genes may also influence tumor behavior, affecting clinical outcomes. The epigenetic silencing of genes that determine tumor invasiveness, growth patterns, and apoptosis, in particular, may dictate tumor recurrence after treatment and affect OS. Because each tumor may harbor multiple genes susceptible to promoter hypermethylation, individual tumors would exhibit different frequencies of methylation profile potentially predictive of a patient's clinical outcome (13, 14). This methylation profile could be of relevance in those tumors in which additional clinical and biological features of prognostic importance are not easily available, as occurs in ETV6/RUNX1-positive BCP-ALL.

Our results indicate that the methylation of multiple genes is a common phenomenon in ETV6/RUNX1-positive BCP-ALL and may be the most important way to inactivate cancer-related genes in this disease; 89% of cases had at least one gene methylated, whereas 63% of cases had three or more genes methylated. Moreover, ETV6/RUNX1-positive patients showed a higher degree of genes simultaneously methylated than ETV6/RUNX1-negative patients, suggesting that methylation plays a more important role in t(12;21) leukemogenesis than in other forms of BCP-ALLs. This issue is interesting in view of recent backtracking studies in twins and triplets, as well as studies of newborn Guthrie blood spots, indicate that the ETV6/RUNX1 fusion occurs in utero and it is necessary but insufficient for leukemogenesis (27). Subsequent unidentified molecular events in early childhood seem necessary for the clinical development of BCP-ALL. Our data suggest that an epigenetic mechanism could be involved in this process.

Our data also show that the methylation in human ETV6/RUNX1-positive cells can participate in the loss of regulation of four key cellular pathways: (a) growth-deregulating events comprising those that target the principal late-G1 cell cycle checkpoint (LATS2, NES1, PTEN, and p73 inactivation); (b) the apoptotic program through inactivation of DIABLO, PTEN, and REPRIMO; (c) the cell-cell adhesion by the inactivation of some members of the cadherin (CDH13 and CDH1) and metalloprotease (ADAMTS1 and ADAMTS5) families; and (d) deregulation of the WNT signaling pathway by inactivation of its antagonists, DKK3, sFRP1, sFRP2, sFRP5, HDPR1, and WIF1. Because the frequencies of methylation of the majority of these genes were similar in ETV6/RUNX1-positive and -negative BCP-ALL, one could speculate that the disruption of these oncogenic pathways is a common phenomenon in all types of childhood lymphoid leukemogenesis. However, a group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive BCP-ALL, suggesting that they play an important role in t(12;21) leukemogenesis.

Some studies have indicated that patients with t(12;21) have an excellent prognosis (2). However, in patients treated with the Berlin-Frankfurt-Munster group protocols, ETV6/RUNX1-positive patients displayed better outcome in short-term follow-up, but seemed to have more late relapses (3–5). Although one possible explanation for these diverging results is that the prognosis effect of this translocation is dependent on therapy, they also indicate that the biological nature of leukemias carrying the ETV6/RUNX1 fusion gene is heterogeneous. However, a global view of gene expression in ETV6/RUNX1-positive BCP-ALL using microarrays was associated with a characteristic and very homogeneous gene expression signature (28). Therefore, it is very difficult to obtain data of prognostic significance using this procedure. In contrast to this, our results show that ETV6/RUNX1-positive BCP-ALL is very heterogeneous from an epigenetic point of view. Aberrant methylation of CpG islands is quantitatively different in individual tumors within the same tumor type, and this patient-specific methylation profile provides important prognostic information in ETV6/RUNX1-positive BCP-ALL patients treated with the same therapeutic protocol and with a long follow-up. The presence in individual tumors of multiple epigenetic events that affect each of the pathways discussed above is a factor of poor prognosis in this disease. Patients with methylation of three or more genes had a poorer DFS and OS than patients with two or less methylated genes. Multivariate analysis confirmed that methylation profile was associated with a shorter DFS and OS. Therefore, methylation profiling in ETV6/RUNX1-positive BCP-ALL could have important clinical information for guiding the selection of therapy and also providing a basis for developing novel therapies, such as demethylation treatment. Because the number of samples analyzed is relatively small, our results should be independently confirmed in a larger series.

In summary, our results indicate that simultaneously aberrant methylation affecting key molecular pathways is a common phenomenon in ETV6/RUNX1-positive BCP-ALL. The methylation profile seems to be an important factor in predicting the clinical outcome of these patients.


   Footnotes
 
Grant support: Fondo de Investigacion Sanitaria (Spain) 03/0141, 01/0013-01, 01/F018, 02/1299; Navarra Goverment (31/2002); RETIC C03/10, Junta de Andalucia 03/143; 03/144 and funds from IMABIS (Malaga, Spain), "UTE project CIMA," Fundación de Investigación Médica Mutua Madrileña Automovilista, and Asociacion Medicina e Investigacion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/24/05; revised 1/10/06; accepted 2/ 7/06.


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Commentary

CpG Island Methylator Phenotype and Childhood Leukemia
Norman J. Lacayo, Jorge F. DiMartino, Michael C. Wei, and Gary V. Dahl
Clin. Cancer Res. 2006 12: 4787-4789. [Full Text] [PDF]



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