UGT2B17 as a disease accelerator in CLL

In this issue of Blood, Gruber and colleagues provide a new potential enzyme involved in chronic lymphocytic leukemia (CLL) progression by identifying uridine diphospho (UDP) glucuronosyltransferase 2B17 (UGT2B17) as both a prognostic marker and therapeutic target.¹ 

CLL is characterized by accumulation of malignant B cells in the blood, bone marrow, and lymphoid tissues and it has a very heterogeneous outcome.²  Multiple prognostic factors have been identified in CLL that predict poor outcome with the biggest drivers being immunoglobulin heavy chain (IgV_H) unmutated status, ZAP-70 protein overexpression, and the presence of select genomic abnormalities [del(17p13.1) and del(11q22.3) or mutations (NOTCH1, SF3B1, and p53)].^2,3  Here, Gruber and colleagues identify for the first time that uridine diphospho (UDP) glucuronosyltransferase 2B17 (UGT2B17) is both overexpressed in CLL tumor cells and that high levels of UGT2B17 mRNA correlate with shorter treatment-free survival and overall survival (see figure). UGT2B17 mRNA levels were effective in further discriminating outcome of patients with of IgV_H mutated but not unmutated patients. In addition, increasing UGT2B17 expression change from baseline to day 3 of treatment after fludarabine and cyclophosphamide (FC) or FC with rituximab identified patients with low response rate to this treatment. Collectively, the findings of this article strongly indicate the role of UGT2B17 as a new prognostic marker and a potential therapeutic target for patients with high-risk CLL.

Notably, the story does not stop here but extends to biology of this important enzyme. UGT2B17 is a member of the uridine diphosphoglucuronosyltransferase (UGT) protein family and catalyzes the glucuronidation of a diverse range of substrates including steroid hormones and lipid-soluble drugs.^4,5  Therapies commonly used in CLL such as those in the FC regimen are not known to be influenced by UGT2B17. Gruber and colleagues preliminarily tried to explore how UGT2B17 might be altering CLL cell biology. By testing the expression of several homolog isoforms of UGTs in CLL patient samples and in the CLL cell line MEC-1, UGT2B17 mRNA expression was the only isoform expressed to any significant level. UGT2B17 mRNA expression was also shown to directly correlate with its enzymatic activity. Extending the biology further, UGT2B17 RNA silencing in the MEC-1 cell line was pursued followed by analysis of comparative microarray that identified several important activation markers including CD38 and CD86. Further phenotype associated with UGT2B17 knockdown as related to proliferation, spontaneous apoptosis, or resistance to fludarabine or the active metabolite of cyclophoshamide (4-HC) was not reported.

The current study is provocative and identifies something entirely new and leaves several questions to be addressed. First, is the UGT2B17 protein expressed in CLL and what does its knockdown do to proliferation and cell survival? The expression of UGT2B17 is investigated only at mRNA level in this article and the MEC-1 cell phenotype after knockdown is not described. Second, what factors induce UGT2B17 overexpression in CLL and what are the direct versus indirect consequences of UGT2B17 overexpression? Although gene-expression profile in the UGT2B17 knockdown MEC-1 cells is described in the article that identify several important genes modified including CD38 and CD86, it is uncertain if this is a direct or indirect consequence of UGT2B17 expression. Finally, how do we translate these findings to clinical applications relevant to CLL patients? UGT2B17 expression may be used as a prognostic marker in CLL; however, therapeutic drugs targeting UGT2B17 have not been investigated. Catechins in green and white tea⁶  and flavonoids from red wine⁷  have been shown to inhibit UGT2B17. These findings may help to design drugs targeting UGT2B17 for CLL therapy. Furthermore, efforts to eliminate induction of UGT2B17 with treatment once the mechanism of this is understood might also be a relevant strategy. Gruber and colleagues are commended for this fine study that provides new leads to pursue progression of CLL and potential drug resistance associated with its treatment.