Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation
Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation
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DOI：
10.1128/mcb.00404-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Hiebert, Scott W.
中科院分区：
文献类型：
--
作者：
Chyla, Brenda J.;Moreno-Miralles, Isabel;Hiebert, Scott W.
虽然已经确定了一些DNA结合的转录因子来控制造血细胞的命运，但只有有限数量的转录辅助抑制因子(如视网膜母细胞瘤蛋白[PRB]和核激素辅助抑制因子[N-COR])与这些功能有关。在这里，我们发现转录辅阻遏子Mtg16(16号染色体上的髓系易位基因)是决定造血祖细胞命运和早期祖细胞增殖所必需的，它是t(16；21)在急性髓系白血病中的靶点。Mtg16的失活使早期髓系祖细胞向粒/巨噬系倾斜，同时减少了巨核-红系祖细胞的数量。此外，Mtg16的失活损害了短期干细胞、多能祖细胞和巨核细胞-红系祖细胞的快速扩张，这些细胞是在造血应激/紧急情况下所需的。这种损伤似乎是增殖失败而不是诱导细胞死亡，因为c-Myc的表达，而不是Bcl2的表达，补充了Mtg16(-/-)缺陷。
While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e. g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16(-/-) defect.