Mortera-Blanco Teresa, Dimitriou Marios, Woll Petter S, Karimi Mohsen, Elvarsdottir Edda, Conte Simona, Tobiasson Magnus, Jansson Monika, Douagi Iyadh, Moarii Matahi, Saft Leonie, Papaemmanuil Elli, Jacobsen Sten Eirik W, Hellström-Lindberg Eva
Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Blood. 2017 Aug 17;130(7):881-890. doi: 10.1182/blood-2017-03-776070. Epub 2017 Jun 20.
Mutations in the RNA splicing gene are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in in 39 of 40 cases (97.5%), combined with and in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal ( mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for mutations targeting lymphomyeloid HSCs and compatible with mutated negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the mutated clone. Upon transplantation into immune-deficient mice, mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring mutated MDS-RS.
RNA剪接基因突变见于超过80%的伴有环形铁粒幼细胞的骨髓增生异常综合征（MDS-RS）患者。我们研究了MDS-RS患者骨髓造血干细胞和祖细胞区室中该基因突变的起源。对单核细胞部分中反复突变的基因进行筛查发现，40例中有39例（97.5%）存在该基因突变，分别有11例（28%）和6例（15%）患者同时伴有其他基因和基因的突变。在所有研究的患者中，单核细胞中鉴定出的所有反复突变都可追溯到表型定义的造血干细胞（HSC）区室，并且也存在于下游的髓系和红系祖细胞中。虽然与先前的研究一致，在成熟B细胞中几乎没有或没有发现克隆性（该基因突变）参与的证据，但在B细胞祖细胞阶段发现了持续的参与，为该基因突变靶向淋系-髓系造血干细胞提供了确凿证据，并且与该基因突变对淋巴系发育产生负面影响相一致。对体外和体内干细胞功能的评估表明，只有造血干细胞而不是所研究的祖细胞群体能够增殖该基因突变的克隆。将其移植到免疫缺陷小鼠后，该基因突变的MDS-RS造血干细胞分化为特征性的环形铁粒幼细胞，这是MDS-RS的标志。我们的研究结果为MDS-RS患者中该基因突变的多能淋系-髓系造血干细胞起源提供了证据，并为从机制和治疗方面探索该基因突变的MDS-RS提供了一个新的体内平台。
