A retrospective analysis was conducted on a MonoMAC syndrome case admitted in October 2022 to the First Affiliated Hospital of Zhejiang University School of Medicine. The patient, a 16-year-old female with a history of persistent monocytopenia and mild anemia for several years, experienced recurrent symptoms of cough, expectoration, and fever, leading to multiple visits to the hospital. The diagnosis of MonoMAC syndrome was confirmed through comprehensive assessments including routine blood tests, pathogen metagenomic sequencing, lung and bone marrow biopsies, and next-generation sequencing of peripheral blood. The patient underwent haploidentical hematopoietic stem cell transplantation, with a smooth course of transplantation, achieving neutrophil engraftment on + 16 d and platelet engraftment on + 17 d, eventually restoring normal monocyte and NK cell counts. MonoMAC syndrome patients often initially present with infectious symptoms, and the diagnosis can be established based on significant monocytopenia in routine blood tests, history of non-tuberculous mycobacterial infections, and GATA2 germline mutations. Allogeneic hematopoietic stem cell transplantation may be required for some patients to improve their prognosis.
回顾性分析浙江大学医学院附属第一医院2022年10月收治的1例MonoMAC综合征病例，女性，16岁，有多年外周血单核细胞数减少及轻度贫血病史，因\"反复咳嗽咯痰伴发热\"在浙江大学医学院附属第一医院多次就诊，最终结合血常规、病原学宏基因组测序、肺穿刺活检、骨髓穿刺活检及外周血二代测序等检查，诊断为MonoMAC综合征，并接受单倍体造血干细胞移植。患者移植过程较顺利，+16 d粒细胞植入，+17 d血小板植入，最终单核细胞数和NK细胞数恢复正常。MonoMAC综合征患者常因感染症状首次就诊，结合血常规中单核细胞明显减低，非结核分枝杆菌感染史、GATA2胚系突变等检查结果可确诊。部分患者需行异基因造血干细胞移植治疗以改善预后。.

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BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology.
METHODS: Three patients with HLH, one with Mycobacterium avium infection, one with Epstein-Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing.
CONCLUSIONS: GATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.

During hematopoiesis, megakaryocytic erythroid progenitors (MEPs) differentiate into megakaryocytic or erythroid lineages in response to specific transcriptional factors, yet the regulatory mechanism remains to be elucidated. Using the MEP‑like cell line HEL western blotting, RT‑qPCR, lentivirus‑mediated downregulation, flow cytometry as well as chromatin immunoprecipitation (ChIp) assay demonstrated that the E26 transformation‑specific (ETS) transcription factor friend leukemia integration factor 1 (Fli‑1) inhibits erythroid differentiation. The present study using these methods showed that while FLI1‑mediated downregulation of GATA binding protein 1 (GATA1) suppresses erythropoiesis, its direct transcriptional induction of GATA2 promotes megakaryocytic differentiation. GATA1 is also involved in megakaryocytic differentiation through regulation of GATA2. By contrast to FLI1, the ETS member erythroblast transformation‑specific‑related gene (ERG) negatively controls GATA2 and its overexpression through exogenous transfection blocks megakaryocytic differentiation. In addition, FLI1 regulates expression of LIM Domain Binding 1 (LDB1) during erythroid and megakaryocytic commitment, whereas shRNA‑mediated depletion of LDB1 downregulates FLI1 and GATA2 but increases GATA1 expression. In agreement, LDB1 ablation using shRNA lentivirus expression blocks megakaryocytic differentiation and modestly suppresses erythroid maturation. These results suggested that a certain threshold level of LDB1 expression enables FLI1 to block erythroid differentiation. Overall, FLI1 controlled the commitment of MEP to either erythroid or megakaryocytic lineage through an intricate regulation of GATA1/GATA2, LDB1 and ERG, exposing multiple targets for cell fate commitment and therapeutic intervention.

OBJECTIVE: To analyze the occurrence of concomitant gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients with CEBPA mutation and its impact on the clinical characteristics and prognosis of the patients.
METHODS: 151 newly diagnosed patients with CN-AML in the Second Hospital of Shanxi Medical University from June 2013 to June 2020 were analyzed retrospectively. 34 common genetic mutations associated with hematologic malignancies were detected by next-generation sequencing technology. The occurrence of concomitant gene mutations in patients with CEBPA positive and negative groups was compared, and the correlation between concomitant mutations in different functional groups and the clinical characteristics and prognosis of CN-AML patients with CEBPA mutation was analyzed.
RESULTS: In 151 patients with CN-AML, 55 (36.42%) were positive for CEBPA mutation (including 36 cases of CEBPAdm and 19 cases of CEBPAsm), of which 41 (74.55%) had co-mutations with other genes. The main mutated genes were GATA2 (25.45%, 14/55), TET2 (21.82%, 12/55), FLT3 (20.00%, 11/55), NRAS (12.73%, 7/55) and WT1 (9.09%, 9/55), etc. Some cases had two or more concomitant gene mutations. Grouping the mutant genes according to their functions showed that CEBPA+ group had lower mutation rates of histone methylation (P =0.002) and chromatin modification genes (P =0.002, P =0.033), and higher mutation rates of transcription factors (P =0.037) than CEBPA- group. In 55 patients with CEBPA+ CN-AML, the platelet count at diagnosis in signaling pathway gene mutation-positive group was lower than that in the mutation-negative group (P =0.005), the proportion of bone marrow blasts in transcription factor mutation-positive group was higher than that in the mutation-negative group (P =0.003), and the onset age in DNA methylation gene mutation-positive group and chromatin modifier mutation-positive group was older than that in the mutation-negative group, respectively (P =0.002, P =0.008). DFS of CEBPA+ CN-AML patients in signaling pathway gene mutation group was shorter than that in signaling pathway gene mutation-negative group (median DFS: 12 months vs not reached) (P =0.034). Compared with DNA methylation gene mutation-negative group, CEBPA+ CN-AML patients with DNA methylation gene mutation had lower CR rate (P =0.025) significantly shorter OS and DFS (median OS: 20 months vs not reached, P =0.006; median DFS: 15 months vs not reached, P =0.049). OS in patients with histone methylation gene mutation was significantly shorter than that in the histone methylation gene mutation-negative group (median OS: 12 months vs 40 months) (P =0.008). Multivariate analysis of prognostic factors showed that the proportion of bone marrow blasts (P =0.046), concomitant DNA methylation gene mutation (P =0.006) and histone methylation gene mutation (P =0.036) were independent risk factors affecting the prognosis.
CONCLUSIONS: CN-AML patients with CEBPA mutation have specific concomitant gene profile, and the concomitant mutations of different functional genes have a certain impact on the clinical characteristics and prognosis of the patients.
UNASSIGNED: CEBPA突变CN-AML伴不同功能基因突变患者的临床特征及预后分析.
UNASSIGNED: 分析CEBPA突变正常核型急性髓系白血病（CN-AML）患者伴随基因突变发生的情况，及其对患者临床特征及预后的影响。.
UNASSIGNED: 回顾性分析2013年6月至2020年6月就诊于山西医科大学第二医院的151例初诊CN-AML患者，通过第二代DNA测序技术检测34种常见血液肿瘤基因突变情况；比较CEBPA+与CEBPA-患者的伴随基因突变发生情况，分析不同功能的基因突变与CEBPA+ CN-AML患者临床特征及预后的相关性。.
UNASSIGNED: 在151例CN-AML患者中共检测到55例（36.42%）CEBPA+突变（包括36例CEBPA双突变，19例CEBPA单突变），其中41例（74.55%）与其他基因存在共突变，主要突变基因为：GATA2 14 例（25.45%）、 TET2 12 例（21.82%）、FLT3 11例 （20.00%）、 NRAS 7例（12.73%）和WT1 5例（9.09%），部分病例同时存在2种及2种以上伴随基因突变。将突变基因按照功能进行分组后发现，CEBPA+组较CEBPA-组具有更低的组蛋白甲基化及染色质修饰基因伴随突变率（P = 0.002，P =0.033）、更高的转录因子基因伴随突变率（P =0.037）。55例CEBPA+CN-AML患者中，伴信号通路基因突变阳性组患者初诊时血小板计数低于突变阴性组（P =0.005），伴转录因子基因突变阳性组的骨髓原始细胞比例高于突变阴性组（P =0.003），伴DNA甲基化基因和染色质修饰基因突变阳性组的发病年龄均明显大于相应突变阴性组（P =0.002，P =0.008）。伴随信号通路基因突变阳性组CEBPA+ CN-AML患者的DFS短于阴性组（12个月vs 未达到）（P =0.034）。伴DNA甲基化基因突变阳性组较阴性组患者具有更低的CR率（P =0.025），且OS和DFS均显著短于阴性组（中位OS：20个月vs 未达到，P =0.006；中位DFS：15个月vs 未达到，P =0.049）。伴组蛋白甲基化基因突变阳性组患者的OS显著短于阴性组（中位OS：12个月vs 40个月）（P =0.008）。多因素分析显示，骨髓原始细胞比例（HR =4.306）、伴DNA甲基化基因突变（HR =9.917）及组蛋白甲基化基因突变（HR =5.764）是影响CN-AML患者预后的独立危险因素。.
UNASSIGNED: CEBPA+CN-AML患者有其特定的伴随基因表达谱，且伴随不同功能基因突变对患者的临床特征及预后有一定影响。.

OBJECTIVE: To investigate the clinical characteristics, coexisting gene mutations and prognosis of acute myeloid leukemia (AML) patients with GATA2 gene mutation.
METHODS: The clinical data of 370 newly diagnosed AML patients treated in our hospital from January 2008 to January 2021 was analyzed retrospectively, the next-generation sequencing technology was used to detect the mutated genes in those patients. The clinical characteristics of AML patients with GATA2 mutations, the co-mutated genes of GATA2 mutations, and the effect of GATA2 mutation on prognosis were analyzed.
RESULTS: A total of 23 patients (6.2%) with GATA2 mutation was detected in 370 AML patients. Compared with GATA2 non-mutation group, patients in GATA2 mutation group were mostly normal karyotypes (P =0.037) and in low-risk cytogenetic stratification (P =0.028). The incidence of CEBPAdm and NRAS in GATA2 mutation group was significantly higher than that in GATA2 non-mutation group (P =0.010, P =0.009). There were no statistically significant differences between the two groups in terms of sex, age, white blood cell count (WBC), platelet count, hemoglobin, bone marrow (BM) blast, induction chemotherapy regimen and CR rate (P >0.05). Among the 23 patients with GATA2 mutation, the most common co-mutated genes were CEBPAdm, NRAS (both 39.1%), NPM1, FLT3, TET2, WT1 (all 17.4%), ASXL1 and IDH1 (both 13.0%). Survival analysis showed that there was no statistical difference in 5-year overall survival (OS) and leukemia-free survival (LFS) rates between patients with and without GATA2 mutations in whole cohort (n=370) (P =0.306, P =0.308). Among 306 patients without CEBPAdm, the 5-year OS and LFS rates in GATA2 mutation group showed an increasing trend compared with GATA2 non-mutation group, but the difference was not statistically significant (P =0.092, P =0.056). Among 64 patients with CEBPAdm, there was no statistically significant difference in 5-year OS rate between the GATA2 mutation group and the GATA2 non-mutation group (P =0.104), but the 5-year LFS rate of the GATA2 mutation group was significantly decreased (P =0.047). Among the 23 patients with GATA2 mutation, 16 cases received the \"3+7\" induction regimen, of which 12 cases received allogeneic hematopoietic stem cell transplantation (allo-HSCT); 7 cases received the \"DCAG\" induction regimen, of which 3 cases received allo-HSCT. The CR rate was not statistically different between the \"3+7\" regimen group and the \"DCAG\" regimen group (P =1.000). The 5-year OS rate and LFS rate in the transplantation group were significantly higher than the chemotherapy group (P =0.021, P =0.020).
CONCLUSIONS: GATA2 mutation is more common in AML patients with normal karyotype and low-risk cytogenetic stratification, and it is significantly associated with CEBPAdm and NRAS co-mutations. The prognostic significance of GATA2 is influenced by CEBPAdm. The choice of \"3+7\" or \"DCAG\" induction regimen in patients with GATA2 mutation does not affect their CR rate, while the choice of allo-HSCT can significantly improved the prognosis compared with chemotherapy only.
UNASSIGNED: 伴GATA2基因突变的急性髓系白血病患者的临床特征及预后分析.
UNASSIGNED: 探讨伴有GATA2基因突变的急性髓系白血病（AML）患者的临床特征、共存突变基因及其对预后的 影响。.
UNASSIGNED: 回顾性分析2008年1月至2021年1月就诊于解放军总医院第一医学中心血液科的370例初诊AML患者的临床资料，应用二代基因测序技术检测其突变基因，分析AML中GATA2突变患者的临床特征、GATA2突变的共变基因及GATA2突变对预后的影响。.
UNASSIGNED: 370例AML患者中，共23例（6.2%）患者检测到GATA2突变。与GATA2未突变组相比，GATA2突变组患者多属于正常核型（P =0.037）且多处于低危细胞遗传学分层（P =0.028）， CEBPAdm、NRAS 在GATA2突变组的发生率显著高于GATA2未突变组（P =0.010，P =0.009），两组在性别、年龄、白细胞数、血小板数、血红蛋白、原始细胞数、诱导方案、CR率方面的差异均无统计学意义（P >0.05）。23例伴有GATA2突变的患者中主要共存基因突变依次为 CEBPAdm、NRAS （均为39.1%），NPM1、FLT3、TET2、WT1（均为17.4%），ASXL1、IDH1（均为13.0%）。生存分析结果显示，在整个队列中，伴GATA2突变组患者与不伴GATA2突变组患者5年总生存（OS）及无白血病生存（LFS）率无统计学差异（P =0.306，P =0.308）；在306例不伴 CEBPAdm的患者中，GATA2突变组患者较GATA2未突变组患者5年OS率及LFS率均有提高趋势，但差异未达统计学意义（P =0.092，P =0.056）；而在64例伴 CEBPAdm的患者中，GATA2突变组患者与GATA2未突变组患者5年OS率无统计学差异（P =0.104），但GATA2突变组患者5年LFS率显著降低（P =0.047）。23例GATA2突变患者中，16例接受“3+7”诱导方案，其中12例接受异基因造血干细胞移植；7例接受“DCAG”诱导方案，其中3例接受移植。“3+7”方案组与“DCAG”方案组相比，CR率无统计学差异（P =1.000）。移植组较化疗组5年OS率及LFS率显著提高（P =0.021，P =0.020）。.
UNASSIGNED: GATA2突变显著多见于核型正常及低危细胞遗传学分层的AML患者，与 CEBPAdm、NRAS 共突变显著相关。GATA2对预后的意义受 CEBPAdm共突变影响。GATA2突变患者诱导方案选择“3+7”方案或“DCAG”方案不影响其CR率，而选择异基因造血干细胞移植相较于化疗能显著改善预后.

Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are \"open\" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin \"pioneering factor\" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.

GATA2 and ZNF148 have both been mapped to chromosome 3q. Pathogenic variants in GATA2 have been associated with immunodeficiency and high risk for myelodysplasia, acute myeloid leukemia, and chronic myelomonocytic leukemia. Gain-of-function variants in ZNF148 have previously been suggested as a mechanism for agenesis of the corpus callosum (ACC). Here, we report a novel 10.4 Mb interstitial deletion on 3q12.33q22.1 including GATA2 and ZNF148 in a child with developmental delay, agenesis of the corpus callosum, and vertebral segmentation defects. With this diagnosis, we were able to suggest preemptive referrals to hematology/oncology and allergy/immunology for close monitoring of early myelodysplasia. We also propose a possible link between ZNF148 loss of function variants and ACC.

UNASSIGNED: Long noncoding RNAs (lncRNAs) are extensively expressed in eukaryotic cells and have been revealed to be important for regulating cell differentiation. Many lncRNAs have been found to regulate erythroid differentiation in the mouse. However, given the low sequence conservation of lncRNAs between mouse and human, our understanding of lncRNAs in human erythroid differentiation remains incomplete. lncRNAs are often transcribed opposite to protein coding genes and regulate their expression. Here, we characterized a human erythrocyte-expressed lncRNA, GATA2AS, which is transcribed opposite to erythroid transcription regulator GATA2. GATA2AS is a 2080-bp long, primarily nucleus-localized noncoding RNA that is expressed in erythroid progenitor cells and decreases during differentiation. Knockout of GATA2AS in human HUDEP2 erythroid progenitor cells using CRISPR-Cas9 genome editing to remove the transcription start site accelerated erythroid differentiation and dysregulated erythroblast gene expression. We identified GATA2AS as a novel GATA2 and HBG activator. Chromatin isolation by RNA purification showed that GATA2AS binds to thousands of genomic sites and colocalizes at a subset of sites with erythroid transcription factors including LRF and KLF1. RNA pulldown and RNA immunoprecipitation confirmed interaction between GATA2AS and LRF and KLF1. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that knockout of GATA2AS reduces binding of these transcription factors genome wide. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and H3K27ac ChIP-seq showed that GATA2AS is essential to maintain the chromatin regulatory landscape during erythroid differentiation. Knockdown of GATA2AS in human primary CD34+ cells mimicked results in HUDEP2 cells. Overall, our results implicate human-specific lncRNA GATA2AS as a regulator of erythroid differentiation by influencing erythroid transcription factor binding and the chromatin regulatory landscape.