小柯机器人

德国弗莱堡大学Marcin W. Wlodarski研究小组近日取得一项新成果。经过不懈努力，他们揭示了SAMD9/SAMD9综合征克隆性造血的临床演化、遗传特征和轨迹。这一研究成果发表在2021年10月7日出版的国际学术期刊《自然-医学》上。

在本研究中，研究人员探究了一个具有临床注释的儿科骨髓增生异常综合征(MDS)数据库（n = 669），以确定SAMD9/9L综合征的患病率、遗传特征、表型、治疗结果和克隆结构。在连续诊断的MDS个体中，谱系SAMD9和SAMD9L遗传突变(SAMD9/9Lmut)占8%，并且与队列中7%的GATA2突变互斥。在SAMD9/9Lmut病例中，难治性血细胞减少症是最普遍的MDS亚型（90%）；获得性染色单体7占38%；57%的患者出现体质异常；28%的患者存在免疫功能障碍。临床结果与种系突变无关。总的来说，67名患者中具有58个不同的种系SAMD9/9Lmut聚类到蛋白质中间区域。尽管计算机预测尚无定论，但94%的 SAMD9/9Lmut抑制了HEK293细胞的生长，并且在CD34⁺细胞中表达该突变体明显诱导了细胞死亡。

此外，研究发现61%的SAMD9/9Lmut患者在接受体细胞遗传拯救(SGR)后会产生克隆造血，其中有95%具有适应不良（单体7±癌症突变），51%具有适应性（回复性UPD7q、体细胞SAMD9 /9Lmut)。最后，骨髓单细胞DNA测序揭示了个体患者的多个竞争性SGR事件。该研究结果表明SGR在SAMD9/9Lmut MDS中很常见，并体现了儿童造血的特殊可塑性。 

据介绍，SAMD9/9Lmut易造成个体患MDS，并具有躯体拯救的倾向。

附：英文原文

Title: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Author: Sahoo, Sushree S., Pastor, Victor B., Goodings, Charnise, Voss, Rebecca K., Kozyra, Emilia J., Szvetnik, Amina, Noellke, Peter, Dworzak, Michael, Star, Jan, Locatelli, Franco, Masetti, Riccardo, Schmugge, Markus, De Moerloose, Barbara, Catala, Albert, Kllay, Krisztin, Turkiewicz, Dominik, Hasle, Henrik, Buechner, Jochen, Jahnukainen, Kirsi, Ussowicz, Marek, Polychronopoulou, Sophia, Smith, Owen P., Fabri, Oksana, Barzilai, Shlomit, de Haas, Valerie, Baumann, Irith, Schwarz-Furlan, Stephan, Niewisch, Marena R., Sauer, Martin G., Burkhardt, Birgit, Lang, Peter, Bader, Peter, Beier, Rita, Mller, Ingo, Albert, Michael H., Meisel, Roland, Schulz, Ansgar, Cario, Gunnar, Panda, Pritam K., Wehrle, Julius, Hirabayashi, Shinsuke, Derecka, Marta, Durruthy-Durruthy, Robert, Ghring, Gudrun, Yoshimi-Noellke, Ayami, Ku, Manching, Lebrecht, Dirk, Erlacher, Miriam, Flotho, Christian, Strahm, Brigitte, Niemeyer, Charlotte M., Wlodarski, Marcin W.

Issue&Volume: 2021-10-07

Abstract: Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n=669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

DOI: 10.1038/s41591-021-01511-6

Source: https://www.nature.com/articles/s41591-021-01511-6

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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