Gata3 restrains B cell proliferation and cooperates with p18INK4c to repress B cell lymphomagenesis.
Gata3 restrains B cell proliferation and cooperates with p18INK4c to repress B cell lymphomagenesis.
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DOI：
10.18632/oncotarget.11746
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发表时间：
2016-09-27
期刊：
影响因子：
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通讯作者：
Pei XH
中科院分区：
文献类型：
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作者：
Liu S;Chan HL;Bai F;Ma J;Scott A;Robbins DJ;Capobianco AJ;Zhu P;Pei XH
GATA 3是一种谱系特异性因子，控制淋巴细胞分化，其在T细胞定型和发育中的功能已被广泛研究。GATA 3通过抑制原T细胞中的B细胞潜能来促进T细胞特化，并且降低的GATA 3表达对于早期B细胞定型是必需的。GATA 3的遗传变异与淋巴瘤易感性相关。然而，GATA 3功能的丧失如何促进B细胞发育并诱导B细胞淋巴瘤仍然是难以捉摸的。在这项研究中，我们发现，杂合子生殖系缺失导致的Gata3的单倍体丢失增加了骨髓（BM）和脾脏中的B细胞群，并减少了胸腺中的CD4 T细胞群，证实了Gata3促进T细胞发育并抑制B细胞发育。我们发现，Gata 3的单倍体丢失减少了胸腺细胞增殖，诱导p18 Ink 4c（p18），CDK 4和CDK 6的抑制剂，但增强了B细胞增殖的BM和脾独立于p18。p18的缺失部分恢复了Gata3缺陷型胸腺细胞增殖，但进一步刺激了BM和脾脏中Gata3缺陷型B细胞增殖。此外，我们发现，在p18缺陷小鼠中Gata 3的单倍体丢失导致B细胞淋巴瘤的发展，当移植到免疫功能低下的小鼠中时，该淋巴瘤能够快速再生肿瘤。这些结果表明，Gata 3缺陷促进B细胞分化和增殖，并与p18丢失协同诱导B细胞淋巴瘤。本研究首次揭示了Gata 3在B细胞淋巴瘤发生中是一种特异性的肿瘤抑制因子。
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.