Differences of the rezeptor expression profile of aggressive lymphoma and GCB-cells and probable influence on clinical outcome Uhl B1, Prochazka KT 1, Wenzl K 1, Hatzl S 1, Greinix HT 1, Beham-Schmid C 2, Neumeister P 1, Deutsch A 1

1 Division of Hematology, Department of Internal Medicine, Medical University of Graz, Austria, 2 Institute of Pathology, Medical University of Graz, Austria

Introduction and aim CCR1 CCR2 CCR3 Results 2 0,4 0,05 1,8 0,35 0,045 1,6 0,04 0,3 Chemokine receptors (CCR) and their ligands have been 1,4 0,035 The expression profile of de novo 0,25 1,2 0,03

1 0,2 0,025 0,8 identified to play an important role in development of 0,15 0,02 DLBCL, tFLs and RS substantially differed from that of GC-B, 0,6 0,015 0,1 0,4 0,01 0,05 * 0,2 ** * 0,005 lymphoid neoplasms. Our aim was to investigate the 0 0 0 with a at least five fold higher expression of 12 of our RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB different expression profiles in de novo diffuse large B-cell CCR4 CCR5 CCR6 investigated CCR (CCR1, CCR2, CCR4, CCR6, CCR7, CCR8, 4,5 5 14 4,5 4 12 lymphoma (DLBCL), follicular lymphoma and Richter 4 3,5 CCR9, CXCR5, CXCR6and XCR1, p< 0.05) in de novo DLBCL, 3,5 3 10 3 2,5 8 2,5 2 syndrome (RS) in comparison to germinal centre B-cells 2 6 tFLs and RS. Interestingly, RS exhibited a different expression 1,5 1,5 4 1 1 ** ** * (GCB) and their probable influence on clinical outcome. 0,5 * 0,5 ** 2 of 13 of the investigated (CCR1, CCR4, CCR5, 0 0 0 RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB CCR6, CCR8, CCR9, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, Material and methods CCR7 CCR8 CCR9 0,7 6 3

0,6 5 2,5 CX3CR1 and XCR1, p< 0.05) compared to tFL and de novo 0,5 We analyzed mRNA expression levels of 19 chemokine 4 2 0,4 3 1,5 DLBCL, with at least 5 fold higher expression of 9 of our 0,3 ** receptors by using RQ-PCR in the aggressive component of 2 1 0,2 * ** * * 0,1 1 0,5 investigated chemokines. Whereas no significant difference 0 0 0 RS (n=16), de novo DLBCL (n=31) and transformed follicular RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB in CCR expression profile between de novo DLBCL and lymphoma (tFL, n=16). Germinal center B-cells (GC-B, n=4) CXCR1 CXCR2 CXCR3 0,0045 0,0025 0,9 0,004 0,8 transformed FL was detected. served as non-neoplastic controls. After this analysis we 0,0035 0,002 0,7 0,003 0,6 0,0015 0,0025 0,5 By comparing the CCR expression of de novo DLBCL and tFL 0,002 0,4 investigated if there is an impact of expression levels on 0,001 0,0015 0,3 0,001 0,0005 0,2 ** to clinical data we observed that high CCR7 and low CCR8 0,0005 0,1 overall survival of patients with transformed FL and de novo 0 0 0 RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB expression were associated with worse overall survival, DLBCL. CXCR4 CXCR5 CXCR6 1 600 200 0,9 180 whereas no association was detected for the other 500 0,8 160

0,7 140 400 0,6 120 chemokines in the survival of de novo DLBCL and tFL. 0,5 300 100

0,4 80 200 0,3 * 60 0,2 ** 40 * 100 ** 0,1 ** 20 0 0 0 RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB Conclusion

CXCR7 CX3CR1 XCR1 Our data indicate that the CCR-expression profile of RS 35 0,09 600 0,08 ** 30 500 0,07 25 0,06 differs substantially from those of non-neoplastic GCB-cells, 400 20 0,05 300 15 0,04 0,03 200 FL, and de novo DLBCL. CCR7 and CCR8 expression level 10 0,02 * 5 100 ** 0,01 ** 0 0 0 were associated with overall survival. Therefore, these RS DLBCL tFL GCB RS DLBCL tFL GCB RS DLBCL tFL GCB

Chemokine receptor expression in Richter syndrome (RS), diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (tFL) compared to non- multiple deregulated CCRs might serve as useful prognostic neoplastic germinal center B-cells (GCB). * = p<0.05 comparing de novo DLBCL, RS and tFL to non-neoplastic GCB-cells. ** = p<0.05 comparing RS to tFL and DLBCL tool and might be a valuable clinical marker.

Significant overall survival differences in DLBCL and tFL in CCR7 high (p=0.08) and CCR8 low (p=0.027) expression.

DGHO Jahrestagung 2019 Oktober 11-14| Berlin, Deutschland