May-June 2011, Volume 8, Issue 3
The Peculiarity of Mediastinal Lymphomas: A Target For Epigenetic Therapy?
Published on: May 02, 2011
Dr. Johnson indicated no relevant conflicts of interest.
Rui L, Emre NCT, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18:590-605.
The sub-classification of aggressive B-cell lymphomas has moved on steadily since just a decade ago, when gene expression profiling first suggested that molecular patterns might correspond to a specific clinical phenotype. One of the entities recognized as distinct early on was primary mediastinal lymphoma (PMBL), but to date there have been few clear indications about the driving events beyond the observation that PMBL appears to cluster with Hodgkin lymphoma (HL) rather than diffuse large B-cell lymphoma (DLBCL).1 One of the most frequent findings on array genomic hybridization is amplification of chromosome 9p24, which was detected in 45 percent of PMBLs but in only 11 percent of activated B-cell type and in 7 percent of germinal center B-cell-type DLBCL.2 This paper describes the characterization of two cooperating genes within this region of amplification that appear to play a key role in lymphomagenesis, a novel mechanism with potential for therapeutic exploitation.
Members of the Lymphoma Molecular Profiling Project consortium, based in the NCI Metabolism Branch, have carried out an elegant series of experiments using a library of short hairpin RNA molecules to knock down the function of each of the potential oncogenes within the amplicon. Their experiments have shown that suppression of three genes was selectively toxic to PMBL and HL cell lines: JAK2, a tyrosine kinase downstream of cytokine receptors; JMJD2C, a dioxygenase that can demethylate histone 3 at lysine 9 (H3K9); and RANBP6, a gene of unknown function. The involvement of JAK2 is interesting because activating JAK2 mutations are key events in myeloproliferative disorders. In this study the authors show that its overexpression leads to an autocrine growth loop via Interleukin-13 and the increased expression of a very significant proportion (16%) of the genes that characterize PMBL.
The most novel observation, however, is the cooperation between JAK2 and JMJD2C, with the former mediating tyrosine phosphorylation on histone 3 tyrosine 41 (H3Y41), and the latter demethylating H3K9, both of which lead to suppression of heterochromatin formation and transcriptional deregulation. One important effect of these events is the expression of c-MYC, a powerful driver of cell cycle and self renewal, whose expression could be suppressed in the cell lines by a JAK2 inhibitor. However, there were many other genes potentially involved, and the add-back experiment with c-MYC did not fully reverse the effects of JAK2 or JMJD2C suppression.
These results are another manifestation of the power of functional genomics, using inhibitory RNA libraries to dissect the precise functions of different genes in malignant cell lines. The surprising finding here was that two genes on the same amplified segment worked together to modify the epigenome of lymphoma. The findings have several potential implications for therapy. First, it is apparent that inhibitors of JAK2 may exert potent cytotoxicity in PMBL and HL, with an unusually large number of target genes apparently dependent on JAK2 for maintenance of the phenotype. Since JAK2 inhibitors are already under study in the clinic for myeloproliferative disorders, there is scope for rapid testing of this approach. Second, the presence of an autocrine growth loop also provides an opportunity for intervention, for example with antibodies to IL-13, which might be expected to suppress the continued activation of the pathway. Finally, it is increasingly clear that epigenetic modification is a potential target for lymphoma therapy, and the development of histone demethylase inhibitors may be usefully pursued in the future for a variety of malignancies with 9p24 amplifications.
back to top
- Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851-862.
- Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA. 2008;105:13520-13525.