PDF(Pubmed)
Abstract：
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.
摘要：
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。出生时具有单等位基因GATA2突变的患者会发展为骨髓增生异常肿瘤（MDS）和急性髓细胞性白血病（AML），而在3-5％的散发性AML病例中报道了获得性GATA2突变。尚不完全了解异常GATA2活性促进MDS和AML的机制。在不同组织类型和测定中识别GATA2的生理水平的广泛有效的抗体的开发将促进在基础生物学和疾病中理解GATA2的努力。这里,我们纯化了抗GATA2多克隆抗体，并产生了多个高特异性的抗GATA2单克隆抗体，对患者骨髓活检进行免疫组织化学（IHC）优化，并分析了GATA2在健康骨髓成人中的表达，MDS,和急性白血病.在健康的骨髓中，在肥大细胞中检测到GATA2，CD34+HSPCs的亚群，E-钙黏着蛋白+红系祖细胞，和巨核细胞。在MDS中,GATA2表达追踪骨髓母细胞百分比，与髓样发育不良和复杂的细胞遗传学呈正相关，并且是总生存期的非独立阴性预测因子。在急性白血病中，GATA2+母细胞百分比与骨髓谱系密切相关，而具有髓样特征的淋巴母细胞和未分化白血病的子集也表达GATA2。然而,AML中GATA2+母细胞的百分比是高度可变的。AML母细胞中GATA2表达升高与外周中性粒细胞减少症和复杂的AML细胞遗传学相关，但与MDS不同，并不能预测生存。
