Stem Cell Research and Application Unit, Department of Biochemistry and Medical, Biotechnology, Calcutta School of Tropical Medicine, 108, C.R Avenue, Kolkata, 700073, West Bengal, India.
Mol Cell Biochem. 2021 Feb;476(2):535-551. doi: 10.1007/s11010-020-03920-6. Epub 2020 Oct 4.
Myelodysplastic syndrome is a heterogenous group of disorder with clonal dysregulated hematopoiesis characterized by bone marrow failure, cytogenetic and molecular abnormalities and variable risk of progression to acute myeloid leukemia (AML). The bone marrow niche plays a major role in maintaining the homeostasis and is often injured by the chemotherapeutic drugs leading to catastrophic consequences like myelodysplastic syndrome. In the present study, we made an attempt to find out the osteoblastic niche related alterations in the myelodysplastic bone marrow through mainly flowcytometric and fluorescent microscopic studies. We have also checked the condition of the myelodysplastic bone through micro computed tomography. The results revealed that the affected osteoblasts of the myelodysplastic bone marrow compelled the hematopoietic stem cell to come out of quiescence and become actively proliferating, and in this scenario the decline in expression of cell adhesion molecules like N-Cadherin, Intercellular adhesion molecule 1 (ICAM) and upregulated focal adhesion kinase (FAK) played a major role. The hike in number of osteoclasts in myelodysplastic cases than control also shattered the balance between bone formation and resorption ratio. We have recorded a dysregulated expression of transcription factors GATA2 and CEBPα (CCAAT-enhancer-binding-protein) in the hematopoietic stem progenitor compartment of the myelodysplastic bone marrow, the main reason behind the presence of abnormal myeloblasts in myelodysplastic cases. Collectively, we can say the coordinated perturbations in the osteoblastic niche, cell adhesion molecules together with the transcription factors has resulted in the uncontrolled proliferation of hematopoietic stem cell, dysregulated myelopoiesis, early trafficking of hematopoietic progenitors to blood compartment and at the same time pancytopenic peripheral blood conditions during the progression of N-Ethyl N Nitroso Urea (ENU) induced myelodysplasia.
骨髓增生异常综合征是一组异质性疾病，其特征为克隆性造血紊乱，表现为骨髓衰竭、细胞遗传学和分子异常，以及向急性髓系白血病（AML）进展的风险可变。骨髓龛在维持内稳态方面起着主要作用，并且经常受到化疗药物的损伤，导致骨髓增生异常综合征等灾难性后果。在本研究中，我们通过主要的流式细胞术和荧光显微镜研究试图找出骨髓增生异常骨髓中的成骨龛相关改变。我们还通过微计算机断层扫描检查了骨髓增生异常的情况。结果表明，骨髓增生异常骨髓中的受影响成骨细胞迫使造血干细胞从静止状态中出来并变得活跃增殖，在此情况下，细胞黏附分子（如 N-钙黏蛋白、细胞间黏附分子 1（ICAM））的表达下降和粘着斑激酶（FAK）的上调起着主要作用。骨髓增生异常病例中破骨细胞数量的增加也打破了骨形成和吸收比率之间的平衡。我们记录了在骨髓增生异常骨髓的造血干细胞祖细胞区室中转录因子 GATA2 和 CEBPα（CCAAT 增强子结合蛋白）的失调表达，这是骨髓增生异常病例中异常原始细胞存在的主要原因。总之，我们可以说成骨龛、细胞黏附分子和转录因子的协调扰动导致了造血干细胞的不受控制增殖、髓系失调、造血祖细胞早期向血液区室转移以及在 N-乙基 N 亚硝基脲（ENU）诱导的骨髓增生异常进展期间全血细胞减少的外周血液状况。
