Laboratory of Hematology, Institut Universitaire du Cancer de Toulouse, France; Universite de Toulouse, Inserm, CNRS, Universite Toulouse III-Paul Sabatier, Centre de Recherches en Cancerologie de Toulouse, Toulouse.
Human Dendritic Cell Laboratory, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.
Haematologica. 2023 Jun 1;108(6):1515-1529. doi: 10.3324/haematol.2022.282250.
Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.
胚系 GATA2 突变易导致骨髓恶性肿瘤，这是由于额外获得的体细胞突变的不断积累。在这里，我们描述了 78 例 GATA2 缺陷患者的临床和生物学特征。造血干/祖细胞表型特征显示髓系祖细胞耗竭。在携带 GATA2 胚系突变的患者中，常发生 STAG2、ASXL1 和 SETBP1 基因突变以及细胞遗传学异常（单体 7、三体 8、der(1;7)）。根据骨髓细胞形态学，患者可分为三种造血谱。在骨髓正常的患者中未检测到体细胞额外突变（谱 0），而在无过多原始细胞的低细胞性和/或骨髓增生异常但无幼稚细胞增多的骨髓中，STAG2 突变介导的克隆性造血较为常见（谱 1）。最后，SETBP1、RAS 通路和 RUNX1 突变主要与白血病转化阶段相关（谱 2），突出了它们在转化过程中的意义。因此，特定的体细胞改变，可能为受影响的细胞提供不同的选择性优势，与 GATA2 综合征的临床/血液学演变相关。我们的研究不仅表明，体细胞基因谱分析将有助于临床医生对患者进行管理，而且还将阐明胚系 GATA2 突变背景下的白血病发生机制。
