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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA172215-05
Application #
9285736
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2013-07-26
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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