Mature B-cell neoplasms include B-cell chronic lymphocytic leukemia (B-CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and splenic marginal zone B-cell lymphoma (SMZL), among others. We found that acadesine, 5-aminoimidazole-4-carboxamide (AICA) riboside, induced apoptosis in B-cell neoplasms and in normal B lymphocytes, but FL samples were resistant. T cells from these patients or from healthy donors were not affected (

Campas et al. Blood 101: 3674, 2003
;
Campas et al. Leukemia 19: 292, 2005
). We have studied the mechanism of acadesine-induced apoptosis. Acadesine uptake and phosphorylation to ZMP are necessary to induce apoptosis. The best known molecular target of ZMP described to date is adenosine monophosphate-activated protein kinase (AMPK). We have analyzed the expression of LKB1, an AMPKK, AMPK isoforms and related proteins in B-CLL cells. B-CLL cells express LKB1, the α1 catalytic isoform of AMPK and both the β1 and β2 isoforms of the β regulatory subunit, but do not express the α2 isoform. Moreover, the AMPK related protein Snark is expressed in B-CLL cells, while Melk and Ark5 are not. Incubation of B-CLL, MCL, SMZL cells with acadesine induces phosphorylation in Thr172 and activation of AMPK, which correlates with induction of apoptosis. Acadesine enters FL cells as it induces phosphorylation of AMPK, however FL cells are resistant to acadesine-induced apoptosis. Moreover, phenformin and metformin induce AMPK phosphorylation but not induce apoptosis in B-CLL cells. The phosphorylation of AMPK is not sufficient for induction of apoptosis by acadesine in B-cell neoplasms. In B-CLL cells, CD40L or TPA, but not IL-4 or SDF1 inhibit acadesine-induced apoptosis. Acadesine inhibit neither AKT phosphorylation induced by TPA, IL-4, SDF1 or CD40L nor basal AKT phosphorylation. Finally, acadesine induces a conformational change in Bax protein, and citochrome c release to cytosol which is not block by ZVAD.fmk. In conclusion, although further studies are necessary to elucidate the mechanism of acadesine-induced apoptosis, we propose that acadesine may provide an effective treatment for mature B-cell neoplasms such as B-CLL, MCL and SMZL.

Topics:
acadesine, apoptosis, b-cell neoplasms, protein isoforms, splenic marginal zone b-cell lymphoma, cd40 ligand, interleukin-4, proto-oncogene proteins c-akt, adenosine, bax protein

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2005, The American Society of Hematology
2005
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