Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK.
Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA 6009, Australia.
Cell Rep. 2021 Oct 26;37(4):109900. doi: 10.1016/j.celrep.2021.109900.
Infant MLL-AF4-driven acute lymphoblastic leukemia (ALL) is a devastating disease with dismal prognosis. A lack of understanding of the unique biology of this disease, particularly its prenatal origin, has hindered improvement of survival. We perform multiple RNA sequencing experiments on fetal, neonatal, and adult hematopoietic stem and progenitor cells from human and mouse. This allows definition of a conserved fetal transcriptional signature characterized by a prominent proliferative and oncogenic nature that persists in infant ALL blasts. From this signature, we identify a number of genes in functional validation studies that are critical for survival of MLL-AF4+ ALL cells. Of particular interest are PLK1 because of the readily available inhibitor and ELOVL1, which highlights altered fatty acid metabolism as a feature of infant ALL. We identify which aspects of the disease are residues of its fetal origin and potential disease vulnerabilities.
婴儿 MLL-AF4 驱动的急性淋巴细胞白血病 (ALL) 是一种预后极差的破坏性疾病。由于对这种疾病的独特生物学特性，特别是其产前起源缺乏了解，因此生存预后未能得到改善。我们对来自人类和小鼠的胎儿、新生儿和成人造血干/祖细胞进行了多次 RNA 测序实验。这使得我们能够定义一个保守的胎儿转录特征，其特征是具有明显的增殖和致癌特性，在婴儿 ALL blasts 中持续存在。从这个特征中，我们在功能验证研究中鉴定了一些对 MLL-AF4+ALL 细胞存活至关重要的基因。特别值得关注的是 PLK1，因为其有现成的抑制剂，以及 ELOVL1，它突出了脂肪酸代谢的改变是婴儿 ALL 的一个特征。我们确定了疾病的哪些方面是其胎儿起源的残留和潜在的疾病脆弱性。
