The T-cell lymphomas, representing approximately 10% of all non-Hodgkin lymphomas, are heterogeneous, poorly understood, and generally associated with a dismal prognosis. The cell of origin for most T-cell lymphoproliferative disorders has remained elusive and represents a barrier to further advances in this field. Normal T cells, under the influence of specific transcription factors, differentiate into functionally disinct populations following antigenic stimulation. For example, GATA-binding protein 3 (GATA-3) is a transcription factor that controls T-cell differentiation into T helper type 2 (Th2) cells. We have shown that myeloid-derived cells are regulated by cytokines transcriptionally regulated by GATA-3 and that these cells, including lymphoma-associated macrophages, promote the growth and survival of malignant T cells. Therefore, we hypothesized that a subset of T-cell lymphomas may be Th2-cell derived and regulate their microenvironment by producing cytokines that are transcriptionally regulated by GATA-3. In support of this hypothesis, we have found that a subset of T-cell lymphomas with an especially poor prognosis expresses GATA-3 and that its expression is associated with clinical and biologic characteristics resembling Th2 cells. Therefore, we aim to test the hypothesis that GATA-3 expression identifies a previously uncharacterized subset of T-cell lymphomas that exploit a GATA-3 driven transcriptional program to regulate lymphoma-associated macrophages within the tumor microenvironment. This hypothesis may support a novel paradigm in tumor biology with implications that extend beyond the T-cell lymphomas. Namely, transcriptional programs that determine cell lineage and differentiation in malignant cells may regulate stromal cells within the tumor microenvironment that are required for tumor growth.
Non-Hodgkin lymphoma is the seventh most common cancer in the United States. Ten to fifteen percent of these are T-cell derived. Unfortunately, the T-cell lymphomas are poorly understood, increasing in incidence, and are associated with a poor prognosis. Improved understanding of their pathogenesis is needed in order to develop better therapeutic strategies.
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|Wang, Tianjiao; Feldman, Andrew L; Wada, David A et al. (2014) GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood 123:3007-15|