GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.
The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.
Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
Tianjiao
T
Wang
Andrew L
AL
Feldman
David A
DA
Wada
Ye
Y
Lu
Avery
A
Polk
Robert
R
Briski
Kay
K
Ristow
Thomas M
TM
Habermann
Dafydd
D
Thomas
Steven C
SC
Ziesmer
Linda E
LE
Wellik
Thomas M
TM
Lanigan
Thomas E
TE
Witzig
Mark R
MR
Pittelkow
Nathanael G
NG
Bailey
Alexandra C
AC
Hristov
Megan S
MS
Lim
Stephen M
SM
Ansell
Ryan A
RA
Wilcox
D015153:Blotting, Western; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009570:Nitriles; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016753:Interleukin-10; C540383:ruxolitinib