Acute Leukemias

Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group

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Adult T-cell acute lymphoblastic leukemia (T-ALL) continues to represent an unfavorable disease. Molecularly based treatment stratifications could help improve outcome. The prognostic impact of HOX11 and HOX11L2 expression has been an area of controversy. We have investigated 286 adult T-ALL patients enrolled into the German Multicenter ALL (GMALL) therapy protocols by comparative real-time RT-PCR. High HOX11 expression and HOX11L2 expression were predominantly seen in thymic T-ALL (P0.031). In a multivariate analysis HOX11L2 expression proved to be an independent adverse risk factor for relapse-free survival (RFS) with a hazard ratio (HR) of 2.02 (P=0.023) and an HR for overall survival (OS) of 1.81 (P=0.021), both adjusted for the immunophenotype. HOX11 expression was found to have a favorable impact on RFS (HR 0.51; P=0.048) but did not exhibit a significant impact on OS. A subgroup analysis for thymic T-ALL revealed a more pronounced negative correlation of HOX11L2 expression with RFS (HR 3.26; P=0.002) and OS (HR 2.38; P=0.009). Although the prognostic impact of HOX11 in T-ALL is less clear, HOX11L2 expression identifies a small subset of high-risk patients, who are so far classified as standard-risk group. Thus, patients with aberrant HOX11L2 expression should be considered early as candidates for intensified treatment regimes.


T-cell acute lymphoblastic leukemia (T-ALL) accounts for about 10–15% of pediatric and 25% of adult ALL cases. Common features of this disease are a high white blood cell (WBC) count, a mediastinal tumor and frequent central nervous system (CNS) involvement.1 Due to sequentially optimized therapeutic regimens, 5-year survival rates have improved steadily up to approximately 50% in adult patients.2, 3, 4 Within T-ALL several prognostic factors have been discussed, including high WBC count, delayed response to induction therapy and immunophenotype.5 The German Multicenter Study Group for Adult ALL (GMALL) has previously demonstrated that the pre- and mature T-ALL immunophenotype are associated with unfavorable outcome, whereas thymic T-ALL represents a favorable subgroup. However, clinical courses vary considerably and point at further heterogeneity of the disease. Understanding this heterogeneity on a molecular level seems to be a key factor for further improving treatment stratifications and modalities. On the basis of observations of recurrent chromosomal translocations involving proto-oncogenes TAL1, LYL1, MLL, LMO1, LMO2, HOX11 and HOX11L2, independent oncogenic pathways and clinically distinctive molecular subtypes of T-ALL have been proposed.6 However, available data are controversial regarding the clinical impact of aberrant HOX11 and HOX11L2 expression in childhood T-ALL, and few data are available in adult patients.7, 8, 9, 10 The pediatric and adult population might differ substantially in the activation status of these oncogenes. Also, little is known about a correlation of molecular data and the immunologic subtypes as an already established prognostic factor.9 Thus, we have retrospectively evaluated the incidence and prognostic impact of HOX11 and HOX11L2 expression in 286 immunologically well-characterized adult T-ALL patients.

Materials and methods

Patients and study material

Study material (bone marrow (BM) and peripheral blood) was derived from pretreated T-ALL patients enrolled in the two consecutive trials 5/93 and 6/99 of the GMALL study group. Therapy details have been previously reported.3 In the 6/99 trial thymic T-ALL patients without additional risk factors were assigned to the standard-risk group, whereas pre- and mature T-ALL patients were assigned to the high-risk group. Scientific investigations were approved by the GMALL study board and complied with the Declaration of Helsinki. Samples were centrally collected, enriched for the blast fraction by density-gradient centrifugation (Ficoll-Paque Plus; Amersham Biosciences, Uppsala, Sweden) and stored in liquid nitrogen. Central immunophenotyping was performed on fresh material at the time of diagnosis using standard procedures. Positive cell-surface antigens showed a fluorescence signal in 20% or more cells. Cytoplasmic/intranuclear antigens were considered positive if 10% or more cells showed a fluorescence signal. The diagnosis of T-ALL required expression of CD7 and cytoplasmic CD3. According to the European Group for Immunophenotyping of Leukemias, classification samples were labeled as pre- T-ALL (CD5+/−, CD2−, sCD3−, CD4−/+, CD8−/+, CD1a− or CD5−, CD2+, sCD3−, CD4−, CD8−, CD1a−), thymic T-ALL (CD5+/−, CD2+/−, sCD3+/−, CD4+/−, CD8+/−, CD1a+) and mature T-ALL (CD5+, CD2+, sCD3+/−, CD4+/−, CD8+/−, CD1a−).

Cell lines, sample preparation and real-time PCR

Isolation of total RNA on cryopreserved material from 286 patients was performed using the RNeasy Mini Kit (Qiagen, Hilden, Germany). cDNA synthesis was performed with random hexamers (Amersham Biosciences, Pittsburgh, PA, USA). Comparative quantitative RQ-PCR was performed on a Rotorgene RG-3000 real-time cycler (Corbett Research, Wasserburg am Inn, Germany) using a Taqman probe. The cell lines ALL-SIL11and HPB-ALL12 were used as positive controls for aberrant HOX11 and HOX11L2 expression, respectively. The relative expression of HOX11 and HOX11L2 was determined using the reference gene ABL as recommended by the Europe against cancer initiative.13 Primer and probe sequences of the target genes were as follows: HOX11-F: 5′-IndexTermGATGGAGAGTAACCGCAGATACAC-3′, HOX11-R: 5-IndexTermTGCGCGGCTTCTTCTTCTT-3, HOX11-P: FAM-IndexTermAGGACAGGTTCACAGGTCACCCCTATCAGA-BHQ1; HOX11L2–F: 5′IndexTermAGACCTGGTTCCAAAACCG-3′, HOX11L2-R: 5′IndexTermGCTGGATGGAGTCGTT-GA-3′, HOX11L2-P: FAM-IndexTermCAGCTGCAACACGACGCCTTCCAA-BHQ1. Each experiment was performed in duplicate and included a nontemplate control, two negative controls (healthy individuals), and a positive control (cell line). The amplification was carried out in a final reaction volume of 25 μl, using 2.5 μl of cDNA and 300 nM primer and 200 nM probe concentration. A hot start PCR was performed with the Absolute QPCR Mix (ABGene, Hamburg, Germany) containing the enzyme Thermo-Start DNA Polymerase with the following cycler program: 95 °C for 15 min (AB-QPCR Mix; ABGene), followed by 60 cycles at 95 °C for 15 s, and 60 cycles at 60 °C for 60 s. The comparative threshold cycle (Ct) method was applied to determine the relative expression levels of the genes of interest (GOI). The cycle number difference ( C t = C t ABL - C t GOI ) was calculated for each replicate. The mean Ct of both replicates was determined and applied to represent the relative expression levels. Samples showing control gene amplification outside the normal range for fresh samples, defined as C t ABL 21 and 30, were excluded from further analysis.13 Positive and negative HOX11L2 groups were determined by a cutoff level of Ct<10 (Ct range −1.2 to 6.4; mean 1.9; standard deviation 2.1). As previously indicated, HOX11 expression is found at both high and low levels.6, 7, 8, 9 The impact of low HOX11 expression has not yet been separately analyzed in adult T-ALL patients. Most studies to date have grouped low-expression samples together with samples not expressing HOX11.8, 9 Fluorescence-activated cell sorting analyses at the time of diagnosis revealed blast counts of 50% or higher in all samples. As a maximum input variation by a factor of two does not sufficiently explain the observed 2–3 log variation in HOX11 expression, we have differentiated between high, low and negative expression. The cutoff was set at Ct<5 for high HOX11 expression (Ct range −4.5 to 2.7; mean −1.2; standard deviation 1.5). Patients with an HOX11 expression of Ct5 were included in the low-expression group (Ct range 5.0–18.7; mean 10.6; standard deviation 3.2). Patients lacking HOX11 expression were classified as HOX11-negative. Expression levels of the applied cell line controls were in range with patient samples at positive HOX11L2 and high HOX11 expression levels.

Statistical analysis

Survival times were measured from the on-study date until the date of death regardless of cause, censoring for patients alive at the time of their last follow-up. Relapse-free survival (RFS) was measured from the time of first complete remission to the date of relapse. Censored were patients with death or drop out in complete remission (CR) as well as patients with stem cell transplantation in first CR or continuous complete remission at the time of last follow-up. Remission status was assessed after completing induction chemotherapy. Complete remission was defined as follows: granulocytes 1500 per μl or higher, platelets of 100 000 per μl or higher, no peripheral blasts, BM cellularity >20% with maturation of all cell lines, <5% BM blasts and no extramedullary leukemia. Primary therapy failure was defined as persistence of peripheral blood blasts or of 25% or more BM blasts after induction therapy. Relapse was defined as the reappearance of circulating blasts, higher than 5% BM blasts or development of extramedullary leukemia. The survival times were analyzed for the different groups, as defined by the expression of HOX11 and HOX11L2, the immunophenotype, the WBC count and the demographic variables. Survival curves of these groups were calculated by the Kaplan–Meier method. The logrank test was used for univariate statistical evaluation of the above-mentioned variables. Multivariate analysis was performed by the Cox regression method, including the variables HOX11 expression, HOX11L2 expression, sex, age, WBC count and the immunophenotype. HOX11 expression was categorized in ‘HOX1-high’ vs ‘HOX11-low or HOX11-negative’. HOX11L2 was classified as ‘HOX11L2-positive’ vs ‘HOX11L2-negative’. The hazard ratio (HR) and 95% confidence interval (CI) were given for the factors of the usable and the final models of both substudies (survival time and remission duration analysis). The final model represents the model with the highest likelihood. The statistical significance of a given variable was assessed by a Wald test. We proved the null hypothesis that two categorical variables are unrelated by doing the χ2-test. Fisher's exact test was used if the expected frequency was below 5 for more than 25% of the cells of a contingency table. The null hypothesis that the age distributions of the groups of HOX11L2 and HOX11 expression do not differ was tested using the Mann–Whitney and Kruskal–Wallis test, respectively. The null hypothesis that the corresponding WBC distributions do not differ was tested accordingly. The cutoff level for statistical significance was set at 0.05. Statistical analysis was performed with the software SPSS for Windows, version 12 (SPSS Inc, Chicago, IL, USA).


HOX11 and HOX11L2 expression and clinical characteristics in adult T-ALL

HOX11 expression was found in 61 patients (21%) at a high and in 57 (20%) at a low level compared to 168 (59%) patients without HOX11 expression. HOX11L2 expression was seen in 27 patients (10%), whereas 255 patients (90%) did not express HOX11L2. Co-expression of HOX11L2 was absent in the high HOX11 subgroup, but was observed in 13 of 286 (5%) low HOX11 patient samples. There were no significant differences regarding gene expression subgroups and CNS involvement, mediastinal mass or pretreatment WBC count (Table 1). Low HOX11 expression was seen more frequently in females, whereas male patients showed rather high or no HOX11 expression (P=0.03). Patients expressing HOX11L2 were significantly younger (median age=20 years) than those who were HOX11L2-negative (median age=30 years; P=0.002).

Table 1 Clinical characteristics according to genetic subgroups

Gene expression status and immunophenotypic data

Immunophenotypic data were available in 282 (99%) of 286 patients (Table 1). Overall, 155 (54%) T-ALL patients showed a thymic, 67 (24%) a pre- and 63 (22%) a mature T-cell immunophenotype. High HOX11 and HOX11L2 expression correlated significantly with the thymic immunophenotype. The majority of samples showed an early cortical stage of differentiation expressing CD2+ (91%), CD1a+ (93%), CD10+ (82%) and either CD4+/CD8+ or CD4−/CD8− (88%). Co-expression of myeloid antigens was infrequent: CD13 was present in 7% and CD33 in 5% of all cases. In HOX11L2-positive samples, a CD2 (74%)-, CD1a (70%)- and CD10 (89%)-positive immunophenotype dominated. HOX11-high compared to HOX11L2-positive samples were different with respect to frequencies of CD34 (HOX11-high 5%; HOX11L2-positive 41%) and CD13 (HOX11-high 7%; HOX11L2-positive 30%) expression (Table 2).

Table 2 Immunophenotype and HOX11/HOX11L2 gene expression status

Treatment response and outcome

The prognostic impact of HOX11 and HOX11L2 gene expression was analyzed in all 286 patients. There was no significant difference seen in complete remission, induction failure and induction death rates among genetic subgroups. RFS was analyzed in 248 patients, who achieved a CR after induction therapy. The Kaplan–Meier survival analysis showed a reduced RFS for HOX11L2 expression (2-year RFS HOX11L2-positive 23 vs 60% HOX11L2-negative patients; Logrank test P=0.0280; Figure 1a) but did not reveal a significant reduction in overall survival (OS) (2-year OS HOX11L2-positive 47 vs 60% HOX11L2-negative patients; Logrank test P=0.0767; Figure 1b). For HOX11 expression an improved OS (2-year OS HOX11-high 76 vs 45% HOX11-low and 57% HOX11-negative patients; Logrank test P=0.0120) and RFS (2-year RFS HOX11-high 73 vs 41% HOX11-low and 53% HOX11-negative patients; Logrank test P=0.0072; Figure 2a) was detected.

Figure 1

Survival analysis for HOX11L2 subgroups in T-cell acute lymphoblastic leukemia (T-ALL). Kaplan–Meier survival analysis for (a) relapse-free survival (RFS) and (b) overall survival (OS) (survival) of adult T-ALL patients demonstrating an inferior outcome of patients with HOX11L2 expression (HOX11L2-positive) vs patients lacking HOX11L2 expression (HOX11L2-negative).

Figure 2

Relapse-free survival (RFS) analysis for T-cell acute lymphoblastic leukemia (T-ALL) subgroups. (a) Kaplan–Meier survival analysis for RFS of adult T-ALL patients showing a favorable outcome for patients with high HOX11 expression vs low and absent HOX11 expression. (b) Kaplan–Meier survival analysis for RFS of adult T-ALL patients showing a superior outcome of thymic vs pre- and mature T-ALL patients.

A multivariate Cox regression analysis produced several usable models including the immunophenotype and the expression of HOX11 or HOX11L2, respectively. It revealed for HOX11L2 expression, adjusted for the immunophenotype, a significant negative prognostic impact (Table 3) on RFS (HR 2.02; 95% CI 1.10–3.70; P=0.023) and—in contrast to univariate analysis—OS (HR 1.81; 95% CI 1.09–3.00; P=0.021). For HOX11 expression, as well adjusted for the immunophenotype, a significant favorable prognostic impact on RFS was found with an HR of 0.51 (95% CI 0.26–0.995; P=0.048), whereas HOX11 expression did not have a significant impact on OS (HR 0.71; 95% CI 0.41–1.24; P=0.234). Regarding the immunophenotype adjusted for HOX11L2, RFS and OS analyses revealed an adverse prognostic impact of pre- and mature T-ALL compared to thymic T-ALL (Figure 2b) with an HR of 2.67 (1.45–4.90; P=0.0016) and 2.70 (1.57–4.65; P=0.0003) for RFS and 2.34 (1.52–3.61; P<0.0005) and 2.55 (1.67–3.90; P<0.0005) for OS, respectively. The Analysis of OS and RFS resulted in the same final model, including the immunophenotype and HOX11L2.

Table 3 Multivariate analysis results of genetic and immunophenotypic variables for relapse-free and overall survival

As HOX11 and HOX11L2 expression were significantly associated with a thymic immunophenotype (Table 1), we have performed a subgroup analysis for the thymic immunophenotype. Overall, 155 thymic T-ALL patients were included in the outcome analysis. Fifty-seven patients showed a high HOX11 expression, 27 a low HOX11 expression and 71 did not express HOX11. HOX11L2 expression was seen in 21 and no HOX11L2 expression was observed in 134 patients. Within these genetic subgroups there were no significant differences seen regarding sex, age, WBC, mediastinal or CNS involvement. The analysis of RFS revealed a trend toward an improved RFS in HOX11-high compared to HOX11-low/-negative patients (2-year RFS 74 vs 59%; Logrank test P=0.055). Regarding OS there was no significant difference between HOX11 subgroups. In contrast, in thymic T-ALL patients HOX11L2 expression was noted to be significantly associated with a reduced RFS (2-year RFS 28 vs 70%; Logrank test P=0.011; Figure 3a) and reduced OS (2-year OS 53 vs 76%; Logrank test P=0.0073; Figure 3b) compared to HOX11L2-negative patients. A Cox regression model restricted to the thymic T-ALL subtype confirmed HOX11L2 expression as strong prognostic factor for inferior RFS (HR 3.26; 95% CI 1.52–6.43; P=0.002) and reduced OS (HR 2.38; 95% CI 1.24–4.56; P=0.009) in thymic T-ALL patients.

Figure 3

Survival analysis for HOX11L2 subgroups in thymic T-cell acute lymphoblastic leukemia (T-ALL). Kaplan–Meier survival analysis for relapse-free survival (RFS) (a) and overall survival (OS) (b) in thymic adult T-ALL patients demonstrating a reduced outcome for patients with HOX11L2 expression (HOX11L2-positive) vs patients lacking HOX11L2 expression (HOX11L2-negative).


Molecularly based subclassifications have led to risk-adopted treatment strategies in a variety of leukemias.14 Similarly, efforts have been made in adult T-ALL to better differentiate a disease of remarkable clinical heterogeneity and improve treatment outcome. The role of aberrant expression of proto-oncogenes HOX11 and HOX11L2 in T-ALL has been an area of controversy. The present analysis of HOX11 and HOX11L2 expression in 286 well-characterized and homogenously treated adult T-ALL patients does confirm and extend previous reports on a negative prognostic impact of HOX11L2 and a positive impact of HOX11 expression.6, 7, 8, 10 In addition, our analyses provides first evidence that the thymic T-ALL subtype can be further divided in a standard-risk and a high-risk subgroup.

The homeobox gene HOX11L2 is located on chromosome 5q35. An aberrant expression of this proto-oncogene was first found in patients with the translocations t(5;14)(q35;q32) and t(5;7)(q35;q21) as well as a t(5;14)(q33;q11).8, 15, 16 HOX11L2 expression is described as the most common genetic finding in pediatric T-ALL with a frequency of approximately 23%. In adolescents it has been found in around 16% and is further declining to 11% in T-ALL patients older than 20 years.8, 9, 10, 18, 19 Reports on the FRALLE protocol with 6 HOX11L2-positive of 28 patients and the Total Therapy studies XI–XIII with 6 HOX11L2-positive of 59 patients revealed a negative prognostic impact of HOX11L2 expression.6, 7 Confirmed were these reports by an analysis of 72 children in the DCOG protocol and 53 children in the COALL protocol.10 In contrast, the largest so far conducted pediatric analysis of 35 HOX11L2-positive of 153 children, enrolled in the EORTC Protocol 58881 and 58951, did not show an adverse impact of this gene expression.8 A recent analysis of 10 HOX11L2-positive of 81 adult T-ALL patients found HOX11L2 expression to be associated with induction therapy failure, failure to respond to a salvage regimen as well as a higher relapse rate and reduced OS.20 Due to the large number of subjects in our study we are able to show an independent negative prognostic impact of HOX11L2 expression by multivariate analysis. Also, we are able to confirm the immunophenotype as strong prognostic factor for RFS as well as OS. Furthermore, we observed an association of HOX11L2 (P=0.031) and HOX11 (P<0.0005) with the cortical immunophenotype, which has been reported previously.6, 7, 8 Cave et al.8 interpreted the high proportion of HOX11L2-positive T-ALL cases with a cortical immunophenoytpe in their study as an indirect argument against a negative impact of HOX11L2 expression. In contrast, we propose that HOX11L2 expression identifies a subgroup of cortical T-ALL with an inferior outcome compared to the majority of cortical T-ALL patients. In contrast to the more powerful method of a COX regression analysis, in a univariate analysis the negative impact of HOX11L2 expression could be obscured by the strong positive impact of the cortical immunophenotype (Figure 1b). A missing adjustment for the immunophenotype could have also accounted for conflicting results of earlier studies.

The proto-oncogene HOX11, located on chromosome 10q24, was first identified in the translocations t(10;14)(q24;q11) and t(7;10)(q35;q24). These translocations result in a juxtaposition of the HOX11 gene to promoter and enhancer elements of T-cell receptor loci.21, 22 The prognostic impact of HOX11 expression and/or translocation t(10;14) in T-ALL has been a matter of debate. In a large pediatric study a positive prognostic impact has been shown for t(10;14).23 Two other studies have indicated a trend toward a better outcome in children with high HOX11 expression.8, 24 Ferrando et al.17 found an improved OS in 16 HOX11-positive of 52 adult patients and suggested that they might be at greater risk from treatment related mortality of allografting. In contrast, two other adult studies with 11 of 81 positive and 6 of 33 positive patients, respectively, have not been able to find a positive impact of HOX11 expression.9, 25 In our study, HOX11 expression was found to be an independent positive predictor of remission duration, but not OS. Although an association of HOX11 expression with the favorable cortical immunophenotype has been described before, our study is the first to control for the effect of the immunophenotype. Furthermore, we have addressed the question whether HOX1l-negative and low HOX11 expression differ prognostically.9 According to our results it seems feasible to combine HOX11-negative and low HOX11-expressing patients to one subgroup. It has been suggested that T-ALL subtypes correspond to different stages in normal thymocyte differentiation as oncogene deregulation can lead to a maturation arrest at a specific stage in thymocyte development.6, 9 In accordance with other studies, we have observed an early cortical maturation level in the majority of HOX11-high positive cases. Our data support the hypothesis that HOX11 deregulation is associated with a uniform cortical thymocyte stage of maturation arrest.9, 18 Such a maturation arrest is observed in pediatric as well as adult patients and is independent of the patients' age. In contrast, our study results confirm an age dependency of HOX11 expression and show a higher incidence of HOX11 expression in adults than in children.9, 18 The underlying mechanisms of HOX11 expression other than translocations are not yet understood. Recent evidence suggests that molecular cytogenetics is able to identify translocations in the vast majority of patients with aberrant HOX11 as well as HOX11L2 expression.10 Which role aberrant HOX11 and HOX11L2 expression play in the multistep process of a leukemic transformation remains to be shown. New data seem to indicate a collaborative action of NOTCH1 mutations and aberrant HOX11 and HOX11L2 expression: although the adverse prognostic effect of NOTCH1 mutations is potentiated by HOX11L2 expression, HOX11 expression seems to attenuate this effect.25

In summary, expression of HOX11 and HOX11L2 is predominantly found in thymic T-ALL. The immunophenotype was confirmed as strong prognostic factor in T-ALL. HOX11 expression does show a weak positive prognostic effect on remission duration, but does not translate in a prolonged OS. In contrast, HOX11L2 expression identifies a small subset of thymic T-ALL patients with shorter remission duration and OS. Thus, patients with aberrant HOX11L2 expression should be considered for intensified treatment regimes, including hematopoietic stem cell transplantation.


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We thank A Sindram, M Molkentin, C Seide, P Havemann, B Komischke and R Lippoldt for their work in the molecular and immuncytologic laboratory in Berlin and R Reutzel from the GMALL study board in Frankfurt, as well as all participating centers of the GMALL therapy study. All authors critically read and made contributions to the paper. UB designed research, analyzed data and wrote the paper. NG (head of the GMALL Study Center), analyzed data and edited the paper. SS performed immunophenotyping and edited the paper. HO performed statistical analysis and wrote statistical part of paper. DH (head of the GMALL Study Group) analyzed data and edited the paper. ET (member of the GMALL Study Group) and TB designed research, analyzed data and edited the paper. The authors have no potential conflict of interests to declare.

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Baak, U., Gökbuget, N., Orawa, H. et al. Thymic adult T-cell acute lymphoblastic leukemia stratified in standard- and high-risk group by aberrant HOX11L2 expression: experience of the German multicenter ALL study group. Leukemia 22, 1154–1160 (2008) doi:10.1038/leu.2008.52

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  • thymic T-ALL
  • HOX11
  • HOX11L2
  • immunophenotype
  • gene expression
  • prognostic marker

Further reading