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 nontoxic adjuvant therapeutic agents such as metformin, melatonin, curcumin, sulforaphane, vitamin D3 and plerixafor, we should be able to target the biology of DLBCL.