Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI.
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI.
Blood Adv. 2024 Jan 9;8(1):80-92. doi: 10.1182/bloodadvances.2023011554.
GATA binding protein 2 (GATA2) is a conserved zinc finger transcription factor that regulates the emergence and maintenance of complex genetic programs driving development and function of hematopoietic stem and progenitor cells (HSPCs). Patients born with monoallelic GATA2 mutations develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML), whereas acquired GATA2 mutations are reported in 3% to 5% of sporadic AML cases. The mechanisms by which aberrant GATA2 activity promotes MDS and AML are incompletely understood. Efforts to understand GATA2 in basic biology and disease will be facilitated by the development of broadly efficacious antibodies recognizing physiologic levels of GATA2 in diverse tissue types and assays. Here, we purified a polyclonal anti-GATA2 antibody and generated multiple highly specific anti-GATA2 monoclonal antibodies, optimized them for immunohistochemistry on patient bone marrow bioosy samples, and analyzed GATA2 expression in adults with healthy bone marrow, MDS, and acute leukemia. In healthy bone marrow, GATA2 was detected in mast cells, subsets of CD34+ HSPCs, E-cadherin-positive erythroid progenitors, and megakaryocytes. In MDS, GATA2 expression correlates with bone marrow blast percentage, positively correlates with myeloid dysplasia and complex cytogenetics, and is a nonindependent negative predictor of overall survival. In acute leukemia, the percent of GATA2+ blasts closely associates with myeloid lineage, whereas a subset of lymphoblastic and undifferentiated leukemias with myeloid features also express GATA2. However, the percent of GATA2+ blasts in AML is highly variable. Elevated GATA2 expression in AML blasts correlates with peripheral neutropenia and complex AML cytogenetics but, unlike in MDS, does not predict survival.
GATA 结合蛋白 2（GATA2）是一种保守的锌指转录因子，可调节驱动造血干细胞和祖细胞（HSPC）发育和功能的复杂遗传程序的出现和维持。出生时携带单等位基因突变的患者会发展为骨髓增生异常综合征（MDS）和急性髓系白血病（AML），而获得性 GATA2 突变在 3%至 5%的散发性 AML 病例中报道。异常 GATA2 活性促进 MDS 和 AML 的机制尚未完全阐明。通过开发广泛有效的抗体来识别不同组织类型和检测中的生理水平的 GATA2，将有助于理解 GATA2 在基础生物学和疾病中的作用。在这里，我们纯化了一种多克隆抗 GATA2 抗体，并生成了多种高度特异性的抗 GATA2 单克隆抗体，对患者骨髓活检样本进行了免疫组织化学优化，并分析了健康骨髓、MDS 和急性白血病成人的 GATA2 表达。在健康骨髓中，GATA2 检测到肥大细胞、CD34+ HSPCs 的亚群、E-钙黏蛋白阳性红系祖细胞和巨核细胞中。在 MDS 中，GATA2 的表达与骨髓原始细胞百分比相关，与骨髓增生异常和复杂细胞遗传学呈正相关，并且是总生存的非独立负预测因子。在急性白血病中，GATA2+原始细胞的百分比与髓系密切相关，而具有髓系特征的淋巴母细胞性和未分化白血病的一部分也表达 GATA2。然而，AML 中 GATA2+原始细胞的百分比高度可变。AML 原始细胞中 GATA2 表达升高与外周中性粒细胞减少和复杂 AML 细胞遗传学相关，但与 MDS 不同，它不能预测生存。
