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Blood, 1 August 2005, Vol. 106, No. 3, pp. 766-767.
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NEOPLASIA
Comment on Moreaux et al, page 1021, and Nishio et al, page 1012
APRIL showers cause CLL and myeloma to flower
John Shaughnessy, Jr
UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES
There is growing evidence that tumor cell growth and survival are intimately associated with signals derived from the microenvironment and, as such, these signals represent therapeutic targets.
Two studies in this issue of Blood expand on this concept by providing evidence that dysregulated B cell–activating factor of the tumor necrosis factor (TNF) family/a proliferation-inducing ligand BAFF/APRIL signaling exists in B-chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM). B-lymphocyte stimulator (BlyS)/BAFF and APRIL are members of the tumor necrosis family of membrane-bound ligands expressed by cells of the monocyte lineage that bind B-cell–specific receptors BAFF-R, B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) to control B-cell maturation and proliferation. A clear link between APRIL signaling and B-cell malignancies came from the observation that mice transgenic for APRIL develop B-1 cell–associated neoplasms.1 Multiple studies have now reported that APRIL and BAFF levels are elevated in the sera of patients with CLL and myeloma and that both autocrine and paracrine APRIL and BAFF signaling exists in these related malignancies.1-5 The 2 papers in this issue focus on the role of accessory cells and paracrine signaling in these diseases. Burger et al originally reported that blood-derived nurse-like cells (NLCs) protect CLL cells from spontaneous apoptosis through stromal cell–derived factor-1 (SDF-1).6 This same group has now discovered that NLCs express BAFF and APRIL and that these molecules can promote CLL cell survival via a paracrine pathway that is distinct from that of SDF-1. Nisho and colleagues discovered that NLCs expressed significantly higher levels of BAFF and APRIL than monocytes and B-CLL cells. The viability of CLL B cells cultured with NLCs was significantly reduced when cultured with a decoy receptor of BCMA, which binds APRIL, and BAFF, but not BAFF-R:Fc, which only binds BAFF. Importantly, the effect of these molecules on survival was additive and distinct from that of SDF-1 , which may be explained by differences in activation of downstream signaling cascades. An important finding is that CLL cells likely use multiple nonoverlapping survival signaling pathways as a means to escape death. It will be interesting to see which other factors NLC produce to promote CLL growth and survival.
In the second report, the Klein laboratory expands on previous work in which they showed that BAFF and APRIL can protect myeloma cells from apoptosis induced by IL-6 deprivation and/or dexamethasone.5 In the current study, Moreaux and colleagues show that the main site of BAFF and APRIL production is in the bone marrow and that, not unexpectedly, this is derived mainly from osteoclasts. Obviously this is of great relevance given that osteoclast numbers are increased in myeloma bone marrow. They also showed that TACI expression varied dramatically in malignant plasma cells. Using supervised hierarchical clustering of global gene expression profiles from 65 primary myeloma samples, they demonstrated that differences in TACI expression could distinguish tumors with a microenvironment-interacting signature versus a plasmablastic signature, suggesting that myeloma expressing high levels of TACI are microenvironment dependent. As with the plasmablastic gene expression signature, patients with the TACIlow signature also had clinical parameters associated with poor prognosis. We eagerly await evidence that survival is indeed different in these two groups.
Although these studies provide us with new and powerful information, they also raise new questions. It will be important to determine if the TACIlow gene expression signature is reflective of a de novo form of the disease or whether all myelomas are TACIhigh and that expression of this gene is lost during disease progression. Longitudinal studies of patients that present with TACIhigh at diagnosis will help answer this question. If this is true, it will be important to understand the genetic mechanisms that compensate for its loss. Will we find activating mutations in downstream signaling components in these cases? Like myeloma, will we find a subset of CLL that are TACI/BCMA/BAFF-R–high and –low expressers? Will we see that there is heterogeneity of APRIL/BAFF responsive and nonresponsive cells in a given CLL or myeloma case? If so, will the degree of heterogeneity be indicative of the stage of disease? Will targeting this signaling system as a therapeutic approach simply select out those cells that are not responsive? Time will tell, but it certainly appears that APRIL "showers" prime the "soil" and promote the "seeds" of CLL and myeloma to "flower." With new therapeutic measures to interfere with this signaling network on the horizon, the question is, can anybody stop the rain? 
References
- Planelles L, Carvahlo-Pinto C, Hardenberg G, et al. APRIL promotes B-1 cell-associated neoplasm. Cancer Cell. 2004;6: 399-408.[CrossRef][Medline]
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- Novak A, Bram R, Kay N, Jelinek D. Aberrant expression of B-lymphocyte stimulator by B-chronic lymphocytic leukemia cells: a mechanism for survival. Blood. 2002;100: 2973-2979.[Abstract/Free Full Text]
- Kern C, Cornuel JF, Billard C, et al. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood. 2004;103: 679-688.[Abstract/Free Full Text]
- Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103: 689-694.[Abstract/Free Full Text]
- Moreaux J, Legouffe E, Jourdan E, et al. BAFF and APRIL protect myeloma cells from apoptosis by interleukin 6 deprivation and dexamethasone. Blood. 2004;103: 3148-3157.[Abstract/Free Full Text]
- Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Blood-derived nurse cells protect chronic lymphocytic leukemia B-cells from spontaneous apoptosis through stromal-derived factor-1. Blood. 2000;96: 2655-2663.[Abstract/Free Full Text]
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