The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.
The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.
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DOI：
10.1182/bloodadvances.2019000554
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发表时间：
2019-08
期刊：
影响因子：
7.5
通讯作者：
Theresa Okeyo-Owuor;Yanan Li;Riddhi M Patel;Wei Yang;Emily B. Casey;Andrew S. Cluster;Shaina N. Porter;D. Bryder;Jeffrey A. Magee
中科院分区：
文献类型：
--
作者：
Theresa Okeyo-Owuor;Yanan Li;Riddhi M Patel;Wei Yang;Emily B. Casey;Andrew S. Cluster;Shaina N. Porter;D. Bryder;Jeffrey A. Magee
MLL重排是引起急性淋巴细胞白血病和急性髓细胞白血病（AML）的易位突变。这些易位可以作为婴儿白血病中唯一的克隆驱动突变发生，表明胎儿或新生儿造血祖细胞可能对MLL融合蛋白的转化非常敏感。为了测试这种可能性，我们使用转基因小鼠在胎儿、新生儿、青少年和成年阶段诱导一种易位产物MLL-ENL。当在胎儿或新生小鼠中诱导MLL-ENL时，几乎所有小鼠都死于AML。相反，当在成年小鼠中诱导MLL-ENL时，尽管持续的转基因表达，但大多数存活>1年。当MLL-ENL在新生儿中诱导时，AML起始是最有效的，并且即使在新生儿中短暂抑制MLL-ENL也可以在大多数小鼠中预防AML。MLL-ENL靶基因在新生祖细胞中比在成年祖细胞中更有效地诱导，这与不同的AML起始效率一致。有趣的是，移植应激减轻了白血病发生的发育障碍。由于胎儿/新生儿祖细胞高度胜任启动MLL-ENL驱动的AML，我们测试了Lin 28 b（胎儿主调节因子）是否可以加速白血病发生。令人惊讶的是，Lin 28 b抑制了AML的发生，而不是加速它的发生，这可能解释了为什么MLL重排经常发生在人类婴儿白血病患者出生前，但转化通常不会发生，直到出生后，当Lin 28 b水平下降。我们的研究结果表明，MLL-ENL驱动的AML启动的效率在产前和产后发育过程中发生变化，发育程序可以被操纵以阻止转化。
MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL-driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL-driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.