GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual’s risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulatedGATA2transcriptional network. Disease progression (GATA2-EB,n= 6) was associated with increasedGATA2mRNA levels, restored expression of the GATA2 targetEZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC,n= 24) or other pediatric MDS subgroups (RCC,n= 17; MDS-EB,n= 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 andEZH2and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.
GATA2缺乏症是一种异质性、多系统性疾病，与骨髓增生异常综合征（MDS）的高风险及其向急性髓系白血病的进展密切相关。目前，GATA2缺乏症中恶性转化的机制尚不清楚，因此需要预测性标志物来评估个体进展风险并指导治疗决策。本研究对57例儿童MDS患者的骨髓活检样本进行了系统分析。我们聚焦于造血功能及造血微环境（包括其微环境），采用多重免疫荧光结合多光谱成像、基因表达谱分析以及多重RNA原位杂交技术。结果显示，GATA2缺乏症患者表现出GATA2转录网络失调。疾病进展（GATA2-EB，n=6）与GATA2 mRNA水平升高、GATA2靶基因EZH2表达恢复以及H3K27me3增加相关。GATA2-EB的进一步特征为抗凋亡蛋白BCL2的高表达，这一特征在GATA2缺乏症伴儿童难治性血细胞减少症（GATA2-RCC，n=24）或其他儿童MDS亚组（RCC，n=17；MDS-EB，n=10）中均未出现。通过对其他BCL2家族成员进行多光谱成像分析，发现GATA2-EB患者的凋亡介质组合（MAC）评分显著升高。综上所述，我们的研究结果揭示了GATA2缺乏症疾病进展的潜在驱动因素，特别是组蛋白三甲基化增加和凋亡失调。此外，BCL2和EZH2的上调以及MAC评分的升高，为在GATA2-EB治疗方案中使用维奈托克和阿扎胞苷提供了有力依据。
肿瘤(癌症)患者之家