Tumors that look for their springtime in APRIL

Critical Reviews in Oncology/Hematology 72 (2009) 91–97

Tumors that look for their springtime in APRIL E. Roosnek a , M. Burjanadze a,b , P.Y. Dietrich c , T. Matthes a , J. Passweg a , B. Huard a,b,∗ b

a Division of Hematology, Geneva University Hospitals, Switzerland Department of Pathology-Immunology, Faculty of Medicine, Geneva, Switzerland c Division of Oncology, Geneva University Hospitals, Switzerland

Accepted 28 January 2009

Contents 1. 2. 3.

4.

5.

APRIL and its multiple receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APRIL production and tissue distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APRIL and tumors at the benchside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Solid tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. B-cell malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APRIL and tumors at the bedside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Solid tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Hodgkin’s lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Non-Hodgkin’s lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Inflammatory cells produce a proliferation inducing ligand (APRIL), one of the most recently cloned members of the tumor necrosis factor (TNF) family. Early experiments implicated APRIL as a promoting factor in the natural course of various cancers, reinforcing the concept that host inflammatory reactions are part of a tumor development. Recent studies have further analyzed the tumor-promoting role of APRIL in patients with solid tumors or with hematological malignancies. Here, we will review the recent literature, and provide evidence that APRIL may be a useful prognostic tool and a potential target in the treatment of some cancers. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Tumor; Inflammation; TNF; APRIL; DLBCL; CLL; Multiple myeloma

1. APRIL and its multiple receptors A proliferation inducing ligand (APRIL, TNFSF-13) is one of the most recently cloned members of the tumor necrosis factor (TNF) superfamily [1,2]. APRIL is closely related ∗ Corresponding author at: Department of Patho-Immunology, Faculty of Medicine, 1 rue michel servet, Geneva, Switzerland. Tel.: +41 22 379 5811. E-mail address: [email protected] (B. Huard).

1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2009.01.006

to another member of the TNF family, the B-cell activation factor (BAFF, TNFSF-13B). Although some BAFF and APRIL functions are similar [3], most of their functions are non-redundant, which is best illustrated by the distinct phenotype of BAFF- and APRIL-deficient mice [4–6]. Furthermore, BAFF has a unique receptor, BAFF-R [7], whereas APRIL interacts with heparan sulfate proteoglycans (HSPG) [8,9]. Expression of BAFF and APRIL is also regulated differently, at least under pathological conditions [10]. Throughout this

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review, we will focus on APRIL and discuss its potential tumor-promoting activity. Like many members of the TNF superfamily, APRIL is a homotrimer with one ␤-stranded extracellular TNF homology domain (THD). APRIL is initially produced as a type II transmembrane protein, and released in the extracellular compartment after cleavage in the Golgi apparatus by furin-like proteases [11]. The early cleavage in the biosynthetic pathway prevents cell surface expression. APRIL has two canonical TNF receptors (TNF-R), the B-cell maturation antigen (BCMA, TNFRSF-17) and the transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI, TNFRSF-13B) [12]. BCMA harbors one cysteinerich TNF-R homology domain (TRHD), while TACI has two. Despite this difference, APRIL/TACI and APRIL/BCMA interactions are similar, since TACI uses only its TRHD most proximal to the membrane for ligand binding [13]. Several independent groups have measured the affinity of APRIL for TACI and BCMA [13–18]. Analysis of the different reports indicates that APRIL binds to TACI and BCMA with a similar affinity, 4 ± 5 nM and 4.5 ± 6.6 nM respectively. APRIL also interacts with heparan sulfate side chains of proteoglycans through a stretch of basic amino acids, present in the secreted product because located directly after the furin cleavage site in the protein sequence [8,9]. HSPG also interact with TACI [19,20]. This complex interaction of ligands and receptors is reminiscent of the binding of fibroblast growth factors (FGFs) and their receptor to HSPG [21]. Hence, much on APRIL signaling may be learnt from the FGF ligands/receptors system that has been extensively studied. Our current understanding on the role of HSPG is that they may serve as physiological cross-linkers that enable the signaling of the otherwise poorly efficient trimeric form of APRIL. This poor signaling efficiency has been circumvented for the production of biologically active recombinant form of soluble APRIL with fusion to cross-linking partners such as a trimeric coiled-coil domain [22], a collagen domain [9], or a constant domain of immunoglobulin [8]. While BCMA is widely accepted as a positive modulator of humoral immunity by giving a survival signal to plasma cells [23], TACI is much more versatile, regulating either positively or negatively humoral immunity. For the positive regulation, it is becoming more and more evident that engagement of TACI is crucial for the induction of Ig switch. This has been observed in in vitro experiments [24], and further demonstrated with the common variable immunodeficiency phenotype in patients with loss of function mutations in TACI [25,26]. The negative regulation was highlighted by the fact that an anti-TACI is able to dampen Ig secretion in in vitro-stimulated B cells [27]. This negative signaling may further explain the unexpected increased number of B cells in TACI-deficient mice [28], that is leading to the occurrence of B-cell lymphoma in aging animals [29]. The molecular context in which TACI transduce its signal may explain the different signaling outcome. Indeed, addition of an anti-HSPG to the anti-TACI reverts the negative signaling of the anti-TACI, and increases Ig secretion [20].

Hence, engagement of HSPG may dictate the outcome of TACI triggering by APRIL, consistent with the fact that these molecules are known to transduce signaling into cells [30], as well as with the fact that TACI engagement by HSPG also delivers a signal on its own [19]. Hence, the multiple signaling receptors that can be engaged by APRIL establish numerous possibilities in APRIL signaling, that are even increased by the fact that HSPG contribution to APRIL signaling may be provided in cis when HSPG are expressed on the responding cells [31], or in trans when HSPG are expressed on adjacent cells or in the extracellular matrix [32]. Taken together, this indicates that the result of APRIL signaling will depend on the APRIL-R phenotype of the responding cells, and can potentially be mechanistically and biologically very different from one cell to another.

2. APRIL production and tissue distribution Early Northern blot studies performed shortly after its cloning reported that APRIL is broadly expressed in diverse tissues, with a high expression in peripheral blood and an intermediate expression in pancreas, small intestine, protaste and ovary [1]. APRIL mRNA was observed in hematopoietic cells from the myeloid lineage [33], but also in megakaryocytes [34], osteoclasts [35], and mesenchymal cells [36]. Furthermore, APRIL mRNA was detected in tumor cells from diverse origins such as solid tumors [2,37,38], Hodgkin and non-Hodgkin B-cell lymphoma (HL and NHL) [31,39], and multiple myeloma (MM) [40]. At that time, it was believed that the tumor cells produced APRIL in an autocrine manner. Two APRIL-specific antibodies have been instrumental to study APRIL expression in situ. One recognizes the Nterminal APRIL fragment, referred to as ‘APRIL stalk’ that remains, after APRIL processing, associated to membranes, mostly located in the inner compartment of producing cells, consistent with the early cleavage of APRIL described in the Golgi [11]. Because the stalk fragment is stable, an anti-stalk antibody can be used to identify APRIL-producing cells [41]. The antibody typically stains CD15+ elastase+ neutrophils in sections from normal lymphoid tissues [32], HL [42], NHL [41] and from solid tumors [43]. In addition, L1 protein+ histiocytes and vimentin+ mesenchymal cells from a minority of NHL tumors are also positive. Tumor cells were negative in the majority of the cases, except for a focal expression observed in rare cases of solid tumors. This in situ analysis indicates that the APRIL mRNA observed in vitro in other myeloid cells, megakaryocytes and tumor cells is not sufficient to produce the APRIL protein to a level high enough for detection by standard immunohistochemistry. Hence, these cells may be a minor source of APRIL in situ. For osteoclasts, it is not yet known whether they express a high level of APRIL in situ, because they were too few in the tissues we analyzed. Despite this lack of knowledge, neutrophils may be viewed as the main cellular source of APRIL in situ in non-bone tissues, and most likely also

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in the bone marrow considering their elevated number in this organ. APRIL production by neutrophils appears constitutive, since the stalk staining obtained for bone marrow, blood and tissue-infiltrating neutrophils is similar. A subset of epithelial [32] and endothelial cells [41] is also positive for the stalk fragment. Epithelial cells produce APRIL after toll-like receptor (TLR) stimulation [32,44], but it is presently not known what triggers APRIL production in endothelial cells. Because endothelial cells from blood vessels draining healthy tissues, such as non-infected tonsils, spleen and lymph nodes are negative (unpublished observations), it is likely that the stimuli are also of inflammatory nature. At the tumor-cell level, the stalk reactivity was not observed in malignant cells from HL (n = 285) and NHL (n = 399) lesions, and in less than 10% (n = 2158) of the solid tumors, showing that autocrine production of APRIL by tumor cells is rare, at least when high expression is considered. In the few positive cases, the stalk reactivity was not homogeneous but focal among the tumor nest, indicating that APRIL production by tumor cells is not constitutive but induced under particular circumstances, perhaps similar to those that trigger epithelial cells. Hence, while APRIL mRNA is widely observed in cultured cells, APRIL protein production in vivo is detected mostly in neutrophils. The second antibody instrumental to the study of in situ APRIL expression recognizes the THD of APRIL. Its reactivity is valuable, because full-length APRIL in producing cells is not detected by conventional immunohistochemistry, most likely because it is processed early in the biosynthetic pathway [11]. Hence, this second antibody detects only secreted APRIL [41]. As a consequence, reactivities against the stalk fragment and the secreted form of APRIL are very different; an anti-stalk antibody results in a uniform cytoplasmic staining of producing cells, while the antibody against the secreted product yields a characteristics pattern of dots that represents secreted APRIL bound to HSPG. APRIL retention by HSPG is very efficient in tissues. As a result, APRIL concentration in nests of HSPG+ tumors can be very high. This observation makes APRIL a strong candidate to impact tumor development in vivo.

3. APRIL and tumors at the benchside

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only receptors potentially involved in the impact of APRIL on solid tumor cells. Previous reports arguing for a role of HSPG on tumor development [47] support this hypothesis. 3.2. B-cell malignancies Because BCMA and TACI are expressed by B cells, it is not surprising to find these receptors in B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantlecell lymphoma (MCL), follicular-cell lymphoma (FCL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) [39,41,48–50]. Expression of these APRIL-Rs varies in patients with the same malignancy. It is likely that the malignant transformation induces aberrant expression of these receptors, since the stage of differentiation for healthy B cells corresponding to some of the lymphomas mentioned above are not known to express TACI and/or BCMA [51]. For instance, BCMA that is uniquely expressed during late B-cell differentiation stages [52] is also observed in tumors originating from earlier stages such as CLL. As a consequence of BCMA and/or TACI expression, established cell lines or cells freshly isolated from B-cell lymphoma patients respond by an increased survival/proliferation in the presence of recombinant APRIL in vitro. This was shown for CLL [48,50], FCL, BL and DLBCL [39]. Activation of the classical NF␬B signaling pathway explains the increased survival/proliferation [53]. This role was further substantiated in vivo with the report that a significant fraction of animals overexpressing an APRIL transgene develops lymphomas, reminiscent of human CLL [54]. The situation is very similar for HL, now considered to originate from B cells, and for multiple myeloma, originating from plasma cells. HL cell lines express TACI and/or BCMA [31,42], and respond to APRIL in vitro by an increased survival as a result of NF␬B-activation also from the classical pathway [31]. MM cells express BCMA uniformly, while their TACI expression is more variable [40]. A survival/proliferation signal by APRIL for MM cells has also been observed in vitro [40]. This role of APRIL on MM cells was substantiated in vivo, since Atacicept, a soluble form of TACI with APRIL antagonistic activity, impaired the survival of fresh MM cells implanted in human bones grafted into NOD/SCID mice [55]. A similar effect was not reproduced with BAFF-R-Ig, antagonizing only BAFF in this setting.

3.1. Solid tumors APRIL was originally described as a factor promoting solid tumor development in an autocrine fashion [1,2,37]. Its tumor-promoting capacity was shown in vitro by addition of recombinant APRIL to tumor cells [2], and in vivo either by APRIL transfection into tumors [2], or by antagonizing endogenous APRIL [45]. However, the identification of BCMA and TACI that are mainly expressed by B cells [46] as the receptors for APRIL raised doubts on the tumorpromoting role for solid tumors. At present, no BCMA/TACI has been detected on solid tumor cells, leaving HSPG as the

4. APRIL and tumors at the bedside Several studies investigated to what extent the survival and/or proliferation signals given by APRIL to tumor cells in experimental models would impact tumor development in patients. Obviously, the tumor-promoting effect of APRIL signaling may be reduced in patients under treatment. The role of APRIL in the clinical outcome of patients was recently studied by two different approaches. In the first approach, APRIL was quantified by immunohistochemistry in biopsies

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of tumor lesions. The results revealed striking differences among patients of otherwise identical histological diagnosis. While lesions of some patient contained high concentrations of broadly distributed secreted APRIL, others contained only a few focally distributed spots or were completely negative. The biological pathway mediating these differences is presently unknown, but it is related to a difference in the number of APRIL-producing neutrophils infiltrating the tissue. In the second approach, APRIL was measured in the serum of patients. This second approach also revealed differences among patients, of whom a significant fraction had serum levels that were significantly higher than those of healthy controls. In the studies reviewed below, both methods have been used to stratify patients according to APRIL expression. 4.1. Solid tumors Tumor lesions of about half of the patients with various solid tumors from a large cohort (n = 2158) showed APRIL upregulation (APRILhigh ) [43]. APRIL expression was not correlated with clinical parameters such as age, stage, and histological grade of the disease. Retrospective analysis of disease-free (DFS) and overall survival (OS) for patients with bladder, ovarian or head and neck carcinoma stratified according to APRIL expression revealed no significant differences [56]. An independent investigation showed that more than 70% of breast cancer patients are APRILhigh [57]. Likewise, APRIL upregulation in these patients was not significantly associated with tumor grade, DFS or OS. The authors did report that APRILhigh primary lesions metastasize more frequently but this warrants further investigation, since only 4 non-metastatic lesions were analyzed. Nevertheless, the observation is intriguing because decreased level of HSPG expression has been associated with metastatic spreading of solid tumors [58]. In lesions with high concentration of a HSPG ligand such as APRIL, internalization from the tumor-cell surface and subsequent degradation of HSPG [59] may well occur. 4.2. Hodgkin’s lymphoma HL, characterized by the Reed–Sternberg tumor cells, is probably one of the clearest examples of the impact of the environment on tumor development. Intralesional APRIL is upregulated in 64% (n = 285) of patients with nodular sclerosis or mixed cellularity [60]. The percentage of APRILhigh patients increases significantly with disease stage, which is consistent with the increased inflammation that is characteristic of late HL stage [61]. APRIL may promote growth of Reed–Sternberg cells that are often tightly associated with APRIL-producing neutrophils [42] and as a consequence, exposed to high concentrations of APRIL. Nevertheless, we found only trends towards lower DFS and OS in APRILhigh patients that did not reach statistical significance [60]. It is noticeable that the impact on survival of a tumor-promoting effect by a single biological marker such as APRIL in

HL patients may be masked by the high treatment efficacy currently achieved in this disease [62]. Indeed, the tumor-promoting capacity of APRIL must be considerable to find a statistically significant impact on survival in the cohort we analyzed, of which 92% of patients were still alive after 15 years. Because we also failed to find a correlation between APRIL expression and the occurrence of relapse, we conclude that it is unlikely that APRIL will become a valuable biological marker for prognosis and/or treatment of HL. 4.3. Non-Hodgkin’s lymphoma APRIL’s role in the clinical development of CLL was studied by measuring serum concentrations of APRIL [63]. Seventy-five percent of CLL patients (n = 95) had higher than normal amounts of APRIL in their blood. The sera of patients with intermediate/advanced Binet stage of disease contained significantly more APRIL than the sera of patients with an earlier stage of disease. Notably, the OS of APRILhigh patients was significantly lower in univariate analysis. In a multivariate analysis, APRILhigh almost doubled the prognostic value of the heavy chain mutational status, or the Binet staging. This clinical study corroborates the preclinical data discussed above, indicating that APRIL may be a valuable biological marker for CLL prognosis and/or treatment. Accordingly, Atacicept was tested in a phase Ib study during which one of the 12 patients with refractory and/or relapsed CLL enrolled showed disease stabilization [64]. To determine the impact on the clinical development of diffuse large B-cell lymphoma, we analyzed APRIL expression in situ. APRIL was upregulated in 46% of DLBCL lesions (n = 56). No significant correlation was found between APRIL upregulation and standard clinical parameters, such as age, disease stage/grade, extranodal involvement, serum LDH, or with the recently defined germinal center and activated B cell subsets in DLBCL [65]. However, the DFS and OS of APRILhigh patients were significantly decreased [41], which appeared to be more pronounced in high-risk patients (unpublished observations). We were able to confirm the decreased survival among high-risk APRILhigh patients in a second independent cohort of 107 patients (manuscript in preparation). In this second cohort, a multivariate analysis demonstrated that the APRILhigh parameter increases the value of the international prognostic index (IPI) by more than two fold. Hence, APRIL signaling in DLBCL may well promote tumor-cell development and decrease patient survival by increasing the resistance of tumor cells to chemotherapy, as He at al. [39] observed in vitro. Atacicept was also tested in 6 patients with DLBCL, but no significant clinical effect was reported [66]. Because APRIL expression is extremely variable among patients, it may be useful to enroll only APRILhigh DLBCL patients in future clinical trials. APRIL has also been monitored in the serum of DLBCL patients [67]. Serum APRIL levels were increased in 50%

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of the patients (n = 66), but only a trend towards a lower progression-free survival (PFS) and OS of APRILhigh patients was found. The apparent contradicting results of these two studies may be owed to the usage of different techniques. In situ APRIL levels do not necessarily correlate with those in serum. As a first example, APRIL is only upregulated in serum from CLL patients but absent from tumor lesions as determined by histochemistry [41] (and manuscript in preparation), and by gene expression array analysis [68]. As a second example, a fraction of DLBCL patients with a high intralesional APRIL expression had no detectable APRIL in their blood [41]. Similar discrepancies between lesion and serum levels have been reported in patients with an autoimmune disease [69]. Obviously, differences in the respective cohorts studied should also be considered. All patients in the studies in which APRIL was quantified in tumor lesions had received CHOP-like chemotherapy only, while the patients in the study reporting serum levels were treated with chemotherapy in combination with Rituximab (R-CHOP). It is conceivable that the effect of APRIL may vanish in patients treated with R-CHOP, a treatment of higher potency than CHOP alone. This has already been shown to overcome resistance conferred by a biological marker [70]. Hence, a study is warranted for the impact of high in situ APRIL expression in the outcome of DLBCL patients receiving R-CHOP. Furthermore, it is noticeable that Kim et al. did not perform stratification into low- and high-risk patients, which, as mentioned previously, may accentuate the correlation between APRIL expression and survival. 4.4. Multiple myeloma APRIL is a crucial factor for the survival of plasma cells [32,71,72], and one might therefore argue that MM would be the malignancy responsive to its tumor-promoting activity. However, no clinical study has been reported on the role of APRIL in the development of MM to date. This may be explained by the difficulties in stratifying patients according to APRIL levels. APRIL production in the bone marrow by maturing granulocytes is constitutive [41]. In addition, there is no important variation in levels of circulating APRIL from one patient to another in order to allow patient stratification [40]. Hence, we believe that a relevant animal model is the only way to test the real APRIL involvement in MM. Although the results with Atacicept in the chemotherapy-free xenograft model [55] were promising, additional experiments are needed to appreciate whether APRIL may be a target in the treatment of MM. We are currently testing APRIL antagonism in a syngeneic mouse model of MM in a regimen associating human drugs. A clinical trial with Atacicept was started in patients with refractory or relapsed MM in 2004. Early results were reported in 2005 on a limited cohort of treated patients with 3/5 patients showing disease stabilization [73]. This promising result warrants further investigation.

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Fig. 1. Survival probability for cancer patients according to APRIL level of expression, 5-year survival probability is shown for patients with the indicated cancers. For CLL, 12-year survival probability is shown. For DLBCL, patients were further stratified according to their IPI (high: 3–4, low: 0–2). Note that for bladder carcinoma, the survival probability of the entire cohort was high.

5. Concluding remarks The inflammatory cytokine APRIL is abundantly present in lesions from diverse tumors and implicated in the natural growth of many tumors, consistent with the current concept that inflammatory reactions constitute an important part of a tumor development. The impact of APRIL on tumor development is likely to depend on the nature of the APRIL-R expressed by tumor cells, with the lowest impact for solid tumors only expressing HSPG, and the highest for B-cell lymphoid neoplasias expressing HSPG but also the canonical APRIL-R, TACI and BCMA. Despite these considerations, clinical studies in cancers harboring an HSPG+ TACI+ or HSPG+ BCMA+ APRIL-R phenotype and strong in situ APRIL expression revealed that the impact of APRIL may vanish with high treatment efficacy. HL is a relevant example in this case. Indeed, HL cells are fully equipped to respond to APRIL signaling, concentration of APRIL can be high in lesions, but the APRILhigh parameter does not modulate the clinical outcome of HL patients. Fig. 1 shows the survival probability when patients are stratified according to APRIL expression for all the tumors analyzed to date by retrospective analyses. Overall, DLBCL and CLL are two disease entities that may be modulated by APRIL. If the current data on decreased survival in APRILhigh patients is confirmed by prospective analyses, this will validate APRIL as a valuable biological marker in disease prognosis, and as a potential target for disease treatment.

Reviewers Prof. Jan Paul Medema, Amsterdam Medical Center, Laboratory of Experimental Oncology and Radiology, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. Dr. Yataro Yoshida, Takeda Sogo Hospital, Department of Hematology, Fushimi-ku, Kyoto, Japan.

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Acknowledgements The authors thank Dr. Henri Dubois-Ferrière/Dinu Lippatti foundation, the Swiss National Science Foundation, the Leenaards foundation and the Jacques und Gloria Gossweiler Stiftung for their financial support.

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Biographies Eddy Roosnek is a Ph.D. He is currently leading a research group in the Hematology unit from the Geneva University Hospital. Maka Burjanadze obtained his Ph.D. in 2007 from the Montpellier University in France. She joined recently the group of Bertrand Huard. Pierre-Yves Dietrich is a M.D. He is professor in the Oncology department from the Geneva University Hospital. Thomas Matthes is a M.D. He is currently leading a research group from the Hematology unit in the Geneva University Hospital. Jakob Passweg is a M.D. He is currently leading the Hematology unit from the Geneva University Hospital. Bertrand Huard is a Ph.D. He is currently leading a research group from the Hematology unit in the Geneva University Hospital.