Morphoproteomics Identifies SIRT1, EZH2 and CXCR4 Pathways in Diffuse Large B-Cell Lymphoma: Therapeutic Implications.

OBJECTIVE

Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin's lymphoma.

METHODS

We applied morphoproteomics to a tissue microarray of DLBCL cases to uncover commonalities in its biology with therapeutic implications. Morphoproteomic analysis of 9 individual cases of classic DLBCL included immunohistochemical probes to detect silent mating type information regulation 2 homolog 1 (SIRT1), enhancer of Zeste homolog 2 (EZH2) and C-X-C chemokine receptor 4 (CXCR4) and their cellular compartmentalization by bright field microscopy.

RESULTS

We detected the expression of SIRT1 in the majority (>50%) of the tumoral nuclei of 8 of 9 cases of DLBCL and of EZH2 expression in the majority (>50%) of the tumoral nuclei in 9 of the 9 cases; and the expression of the tumoral stem cell marker, CXCR4 in the cytoplasmic and/or plasmalemmal compartment at >50% of the tumor cells in all 9 cases of DLBCL. The morphoproteomic findings of SIRT1 and EZH2 expression in DLBCL, for the most part, parallel the morphoproteomic findings in B-cell acute lymphoblastic leukemia. This concordance has pharmacogenomic and therapeutic implications. Similarly, the fact that EZH2 can enhance the expression of tumoral stem cell marker, CXCR4 implies that there is a block in differentiation in DLBCL.

CONCLUSION

By targeting the Sirt1, EZH2 and CXCR4 pathways using relatively non-toxic adjuvant therapeutic agents such as metformin, melatonin, curcumin, sulforaphane, vitamin D3 and plerixafor, we should be able to target the biology of DLBCL.