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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Subcommittee G - Education (NCI)
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Jakowlew, Sonia B
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Briski, R; Feldman, A L; Bailey, N G et al. (2014) The role of front-line anthracycline-containing chemotherapy regimens in peripheral T-cell lymphomas. Blood Cancer J 4:e214
Iqbal, Javeed; Wright, George; Wang, Chao et al. (2014) Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123:2915-23
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