The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.
The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.
复制标题
多能性调节因子 PRDM14 需要造血调节因子 CBFA2T3 来引发小鼠白血病。
DOI：
10.1158/1541-7786.mcr-18-1327
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Justice,MonicaJ
中科院分区：
文献类型：
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作者：
Tracey,LaurenJ;Brooke-Bisschop,Travis;Jansen,PascalWTC;Campos,EricI;Vermeulen,Michiel;Justice,MonicaJ
含有PR结构域的14（Prdm 14）是胚胎干细胞身份和原始生殖细胞特化的多能性调节剂。PRDM 14基因在人类肿瘤中常被扩增，导致错误表达。小鼠造血干细胞（HSC）中的PRDM 14表达导致T细胞急性淋巴细胞白血病（T-ALL）发生前的祖细胞扩增，这与PRDM 14在肿瘤发生中的作用一致。在这里，我们展示了PRDM 14体内驱动白血病的机制。质谱分析揭示了新的PRDM 14-蛋白质相互作用，包括组蛋白H1，RNA结合蛋白，和主造血调节CBFA 2 T3。在小鼠白血病细胞中，CBFA 2 T3和PRDM 14独立于相关ETO家族成员CBFA 2 T2（PRDM 14在多能细胞中的主要蛋白质伴侣）缔合。CBFA 2 T3在HSC自我更新和谱系定型中起关键作用，并参与急性髓性白血病的致癌易位。这些结果表明PRDM 14将CBFA 2 T3募集到DNA中的模型，导致基因失调，导致祖细胞扩增和T-ALL发展之前的谱系扰动。令人惊讶的是，Prdm 14诱导的T-ALL在Cbfa 2 t3缺陷的小鼠中不发生，表明Cbfa 2 t3是白血病发生所必需的。此外，T-ALL在Cbfa 2 t3杂合子中发展具有显著更长的潜伏期，表明PRDM 14相关的T-ALL对Cbfa 2 t3水平敏感。我们的研究强调了致癌蛋白如何使用祖细胞中的天然蛋白质来引发白血病，为PRDM 14驱动的其他细胞类型的肿瘤发生提供了见解。ImplicationsThe pluripotency regulator PRDM 14 requires the master hematopoietic regulator CBFA 2 T3 to initiate leukemia in progenitor cells，证明了CBFA 2 T3的致癌作用，并为靶向癌症引发细胞提供了途径。
PR domain–containing 14 (Prdm14) is a pluripotency regulator central to embryonic stem cell identity and primordial germ cell specification. Genomic regions containingPRDM14are often amplified leading to misexpression in human cancer.Prdm14expression in mouse hematopoietic stem cells (HSC) leads to progenitor cell expansion prior to the development of T-cell acute lymphoblastic leukemia (T-ALL), consistent with PRDM14's role in cancer initiation. Here, we demonstrate mechanistic insight into PRDM14-driven leukemiasin vivo. Mass spectrometry revealed novel PRDM14–protein interactions including histone H1, RNA-binding proteins, and the master hematopoietic regulator CBFA2T3. In mouse leukemic cells, CBFA2T3 and PRDM14 associate independently of the related ETO family member CBFA2T2, PRDM14's primary protein partner in pluripotent cells. CBFA2T3 plays crucial roles in HSC self-renewal and lineage commitment, and participates in oncogenic translocations in acute myeloid leukemia. These results suggest a model whereby PRDM14 recruits CBFA2T3 to DNA, leading to gene misregulation causing progenitor cell expansion and lineage perturbations preceding T-ALL development. Strikingly,Prdm14-induced T-ALL does not occur in mice deficient forCbfa2t3, demonstrating thatCbfa2t3is required for leukemogenesis. Moreover, T-ALL develops inCbfa2t3heterozygotes with a significantly longer latency, suggesting that PRDM14-associated T-ALL is sensitive toCbfa2t3levels. Our study highlights how an oncogenic protein uses a native protein in progenitor cells to initiate leukemia, providing insight into PRDM14-driven oncogenesis in other cell types.ImplicationsThe pluripotency regulator PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells, demonstrating an oncogenic role for CBFA2T3 and providing an avenue for targeting cancer-initiating cells.