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Blood, 1 July 2008, Vol. 112, No. 1, pp. 1-2.
Signals that maintain leukemic cell viabilityRUSH UNIVERSITY MEDICAL CENTER
Although integrins and cytokines have been reported as triggers for preventing apoptosis and maintaining viability of CLL cells in vivo, evidence presented here by Muzio and colleagues suggests that self-antigens may be responsible for this activity in a subset of CLL patients. They describe signaling characteristics that simulate anergic B cells in mice. In addition, their findings do not support the hypothesis that mutation frequency defines anergy in leukemic B cells.
CD5+ B cells can be considered a component of the innate immune system, producing antibodies with limited diversity. While CD5+ B cells produce our natural antibodies against infectious organisms, some may produce autoantibodies instrumental in scavenging apoptotic cells.7 CLL results from the leukemic transformation of CD5+ B cells. The majority of CLL cells do not proliferate but accumulate as activated cells stuck in G0/G1 stage of the cell cycle. The signals that keep CLL B cells alive in vivo have fascinated us because, upon removing leukemic cells from the body, they undergo apoptosis—as if something within the body were required to prevent their apoptosis. We have suggested that the β2-integrin CD11b serves as one trigger to maintain CLL viability in vivo.8 Cytokines and self-antigens are other potential triggers. Self-antigen stimulation of leukemic B cells in CLL has been a significant subject of investigation. Muzio et al provide evidence that leukemic B cells in a subset of CLL patients have an anergic phenotype, similar to that described in mouse models. Anergic B cells are self-antigen–specific B cells that have been activated, but become unable to proliferate and differentiate into plasma cells as a result of chronic receptor stimulation by low-affinity self-antigens.9 Anergic B cells in mice demonstrate activated signal transduction, particularly via the Erk1,2 and NFAT1 pathways. Normally, antigen-specific B-cell receptor engagement causes activation of PI3 kinase with downstream activation of the Akt survival pathway and cell proliferation. Anergic B cells also have limited life spans and readily undergo apoptosis unless they are constantly challenged with self-antigen. Chronic self-antigen stimulation, then, could be responsible for maintaining viability of CLL leukemia in a subset of patients. Currently, the use of an anergic molecular signature to define CLL patient subsets may not be relevant to clinical management of their disease, as the Akt versus Erk1,2 signaling subsets apparently do not account for prognostic differences as do IgVh mutational signatures. Approximately half of patients with phosphorylated Erk1,2 and half of those with phosphorylated Akt are defined by Muzio et al as having mutated IgVh (see figure). The other half have unmutated IgVh signatures. The authors further report that these molecular signatures of anergy also do not correlate with expression of either CD38 or ZAP70. The main take-home message implicit in these findings and in the investigation of signal transduction pathways is that potential targeted therapy for a given patient should be chosen depending upon defining the nature of the specific pathways activated in their leukemic cells.
Acknowledgment:
J.P. is supported in part by the Wadsworth Foundation.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
reportedly is a major component in resistance to apoptosis,
2% of nucleotides differ from germ-line sequences while another half have unmutated IgVh chains (< 2% nucleotide differences). These signatures likely reflect encounters with antigen and the presence or absence, respectively, of costimulatory molecules in their environment before leukemic transformation. Evidence for self-specificity of leukemic cells is mounting, including data from this article indicating that half of the CLL patients in each subset display an anergic signature (ie, constitutive pErk1,2 expression); that likely results from low-affinity self-antigen encounter.