Non-coding RNAs including small nucleolar RNAs (snoRNAs) play important roles in leukemogenesis but the relevant mechanisms remain incompletely understood. We performed snoRNA focused CRISPR-Cas9 knockout library screenings which targeted the entire snoRNAnome and corresponding host genes. The C/D box containing SNORD42A was identified as an essential modulator for AML cell survival and proliferation in multiple human leukemia cell lines. In line, SNORD42A was consistently expressed at higher levels in primary AML patient samples than in CD34+ progenitors, monocytes and granulocytes. Functionally, knockout of SNORD42A reduced colony formation capability and inhibited proliferation. The SNORD42A acts as a C/D box snoRNA and directs 2´-O-methylation at Uridine 116 of 18S rRNA. Deletion of SNORD42A decreased 18S-U116 2´-O-methylation which was associated with a specific decrease in the translation of ribosomal proteins. In line, the cell size of SNORD42A deletion carrying leukemia cells was decreased. Taken together, these findings establish that high level expression of SNORD42A with concomitant U116 18S rRNA 2´-O-methylation is essential for leukemia cell growth and survival.

中文翻译：

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急性髓系白血病细胞增殖需要 SNORD42A 对 18S 核糖体 RNA 的位点特异性甲基化

包括小核仁 RNA (snoRNA) 在内的非编码 RNA 在白血病发生中发挥重要作用，但相关机制仍未完全了解。我们进行了针对整个 snoRNAnome 和相应宿主基因的以 snoRNA 为重点的 CRISPR-Cas9 敲除文库筛选。含有 SNORD42A 的 C/D 盒被鉴定为多种人类白血病细胞系中 AML 细胞存活和增殖的必需调节剂。与 CD34+ 祖细胞、单核细胞和粒细胞相比，SNORD42A 在原发性 AML 患者样本中始终以更高的水平表达。从功能上讲，敲除 SNORD42A 会降低集落形成能力并抑制增殖。SNORD42A 充当 C/D 盒 snoRNA，并在 18S rRNA 的尿苷 116 处引导 2´-O-甲基化。SNORD42A 的缺失降低了 18S-U116 2´-O-甲基化，这与核糖体蛋白翻译的特定减少有关。在线，携带白血病细胞的 SNORD42A 缺失的细胞大小减少。总之，这些发现表明 SNORD42A 的高水平表达以及伴随的 U116 18S rRNA 2´-O-甲基化对于白血病细胞的生长和存活至关重要。