Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells. Splenocytes were isolated from genetically engineered Mll-AF9 mice that are either Rpl22 proficient or Rpl22 deficient. After sorting for CD11b+Gr1+ leukemic blasts, RNA was isolated, and library preparation was performed using Illumina mRNA stranded kit. Libraries were pooled and sequenced on the NextSeq 2000 platform

本研究报道，核糖体蛋白RPL22的表达在人类骨髓增生异常综合征（myelodysplastic syndrome, MDS）与急性髓系白血病（acute myelogenous leukemia, AML）中频繁下调；RPL22表达下调与不良预后相关。Rpl22基因缺失小鼠表现出类骨髓增生异常综合征的特征，并加速发生白血病。Rpl22缺陷小鼠还表现出造血干细胞（hematopoietic stem cell, HSC）自我更新能力增强、分化潜能受阻，该表型并非源于蛋白质合成减少，而是由于其靶基因ALOX12的表达上调——ALOX12是脂肪酸氧化（fatty acid oxidation, FAO）的上游调控因子。Rpl22缺失介导的脂肪酸氧化增强同样存在于白血病细胞中，并可促进其存活。综上，本研究结果表明，RPL22表达不足通过对其靶基因ALOX12的非经典去抑制作用，增强造血干细胞的白血病转化潜能，而ALOX12介导的脂肪酸氧化增强这一过程，可作为RPL22低表达的MDS与AML白血病细胞的治疗靶点。本研究从基因工程改造的Mll-AF9小鼠中分离脾细胞，这些小鼠分别为Rpl22功能正常型或Rpl22缺陷型；分选得到CD11b+Gr1+白血病母细胞后，提取RNA并使用Illumina链特异性mRNA建库试剂盒进行文库制备；将文库混合后，在NextSeq 2000测序平台上进行测序。