Abstract
GATA3, a lineage specifier, controls lymphoid cell differentiation and its function in T cell commitment and development has been extensively studied. GATA3 promotes T cell specification by repressing B cell potential in pro T cells and decreased GATA3 expression is essential for early B cell commitment. Inherited genetic variation in GATA3 has been associated with lymphoma susceptibility. However, it remains elusive how the loss of function of GATA3 promotes B cell development and induces B cell lymphomas. In this study, we found that haploid loss of Gata3 by heterozygous germline deletion increased B cell populations in the bone marrow (BM) and spleen, and decreased CD4 T cell populations in the thymus, confirming that Gata3 promotes T and suppresses B cell development. We discovered that haploid loss of Gata3 reduced thymocyte proliferation with induction of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, but enhanced B cell proliferation in the BM and spleen independent of p18. Loss of p18 partially restored Gata3 deficient thymocyte proliferation, but further stimulated Gata3 deficient B cell proliferation in the BM and spleen. Furthermore, we discovered that haploid loss of Gata3 in p18 deficient mice led to the development of B cell lymphomas that were capable of rapidly regenerating tumors when transplanted into immunocompromised mice. These results indicate that Gata3 deficiency promotes B cell differentiation and proliferation, and cooperates with p18 loss to induce B cell lymphomas. This study, for the first time, reveals that Gata3 is a tumor suppressor specifically in B cell lymphomagenesis.
Highlights
Altered cell differentiation has long been observed during tumorigenesis and poor differentiation is strongly linked to worse prognosis
These results indicate that Gata3 deficiency promotes B cell differentiation and proliferation, and cooperates with p18 loss to induce B cell lymphomas
Though the percentage of the splenic CD3+ T cell population was significantly decreased in Gata3+/− spleens relative to WT agematched counterparts (32.0% ± 7.7% vs. 42.8% ± 3.8%, Figure 1B), the absolute numbers of splenic CD3+ T cells were comparable between Gata3+/− and WT spleens (25.42 × 106 vs. 25.41 × 106, Figure 1B and Supplementary Figure S3B), suggesting that the percentage decrease of splenic CD3+ T cells in Gata3+/− spleens are relative to the increase of splenic B cells
Summary
Altered cell differentiation has long been observed during tumorigenesis and poor differentiation is strongly linked to worse prognosis. The molecular mechanism of how altered differentiation is linked to tumorigenesis is poorly understood. GATA3, a lineage specifier, is critical in regulating self-renewal of hematopoietic stem cells [3,4,5], and controlling lymphoid cell differentiation [6, 7]. The function of GATA3 in T cell commitment and development has been extensively studied [6,7,8,9]. Clinical studies revealed that somatic mutations in GATA3 were frequently detected in early T cell precursor acute lymphoblastic leukemia [13] and that inherited genetic variation in GATA3 is associated with susceptibility to developing lymphoma and acute lymphoblastic leukemia [14, 15], suggesting that GATA3 may play an important role in suppressing lymphoid malignancies
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