In this inaugural issue of 2010, one paper and an invited commentary serve as a revisit of a subject we discussed back in 2006.1 Specifically, we had previously discussed data that CALLA functions as a suppressor gene. Moreover, it appears to be regulated by virtue of it being a substrate for phosphorylation by casein kinase II (protein kinase CK2). Importantly, we also noted that in all the years that we have been using CALLA as a marker for B-lineage leukemia we do not know the status of its functional activity. That is, it is simply an antigen for our pathologists to use in classifying a disease. However, as we reviewed, it has multiple biochemical effects including interacting with PTEN with subsequent downregulation of Akt and the peptidase activity is capable of cleaving a number of substrates including bombesin, endothelin-1, enkephalin, and more.1 The 6 original references from the first commentary1 and a 2009 review are listed here as numbers 2–7 and,8 respectively.
Here, Ikawa et al9 showed that the CALLA gene is hypermethylated in 4 cases of infant MLL. Thus, its expression is silenced. Dr Nanus and a colleague,10 who have done much detailed work on effects of CALLA in prostate cancer have provided their interpretation of this new finding in a brief commentary that accompanies the article.
If indeed CALLA is a suppressor gene, whether the gene is hypermethylated or the protein is phosphorylated, the end result may be the same: No CALLA activity. As we discussed in 2006, CALLA is inactivated by protein kinase CK2; also known as casein kinase II. Recently, the kinase has been shown to be increased in some patients with AML and inhibitors cause apoptosis11 in vitro.
We suggested in the 2006 paper that protein kinase CK2 inhibition and ascertaining the function of CALLA might be useful. Here, as suggested by Drs Papandreou and Nanus in the case of dense hypermethylation, an obvious strategy would be to use hypomethylating agents such as aza- or deoxyazacytidine. As an aside, we could speculate that one mechanism for the success of maintenance therapy in ALL is that we have been causing some hypomethylation simply by using methotrexate, an antifolate that potentially limits one carbon pool which decreases the supply of S-adenosylmethionine, a universal methyl donor and therefore alters the gene expression.
For whatever the ultimate reason, the new data presented by Ikawa et al allow us to suggest once again that “chasing” CALLA functions as a target rather than simply using it as a marker, is important in the treatment of at least some of our patients with leukemia, now of multiple lineages.
Barton A. Kamen, MD, PhD
Robert Wood Johnson Medical School, New Brunswick, NJ
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2. Houser S. Casein kinase 2 inhibits neutral endopeptidase enzyme activity. Proc Am Assoc Cancer Res. 2006;47:196.
3. Sumitomo M, Shen R, Nanus DM. Involvement of neutral endopeptidase in neoplastic progression. Biochim Biophys Acta. 2005;1751:52–59.
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6. Ganju RK, Shpektor RG, Brenner DG, et al. CDlO/neutral endopeptidase 24.11 is phosphorylated by casein kinase II and coassociates with other phospho-proteins including the Lyn Src-related kinase. Blood. 1996;88:4159–4165.
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8. Trembley JH, Wang G, Unger G, et al. Protein kinase CK2 in health and disease: CK2: a key player in cancer biology. Cell Mol Life Sci. 2009;66:1858–1867.
9. Ikawa Y, Sugimoto N, Koizumi S, et al. Dense methylation of type 1 and type 2 regulatory regions of the CD10 promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene. J Pediatr Hematol Oncol. 2010;32:4–10.
10. Papandreou CN, Nanus DM. Is methylation the key to CD10 loss? J Pediatr Hematol Oncol. 2010;32:2–3.
11. Kim JS, Eom JI, Cheong JW, et al. Protein kinase CK2 alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res. 2007;13:1019–1028.