Centis F, Tabellini L, Lucarelli G, Buffi O, Tonucci P, Persini B, Annibali M, Emiliani R, Iliescu A, Rapa S, Rossi R, Ma L, Angelucci E, Schrier S L
Unità Operativa Ematologia e Centro Trapianto di Midollo Osseo, Ospedale di Muraglia, Azienda Ospedale 'S. Salvatore' Pesaro, Italy.
Blood. 2000 Nov 15;96(10):3624-9.
Beta-thalassemia major is characterized by ineffective erythropoiesis leading to severe anemia and extensive erythroid expansion. The ineffective erythropoiesis is in part due to accelerated apoptosis of the thalassemic erythroid precursors; however, the extent of apoptosis is surprisingly variable. To understand this variability as well as the fact that some patients undergoing allogeneic marrow transplantation are resistant to the myeloablative program, we attempted more quantitative analyses. Two groups of patients totaling 44 were studied, along with 25 healthy controls, and 7 patients with hemolysis and/or ineffective erythropoeisis. By 2 flow cytometric methods, thalassemic erythroid precursors underwent apoptosis at a rate that was 3 to 4 times normal. Because thalassemic marrow has between 5- to 6-fold more erythroid precursors than healthy marrow, this translated into an absolute increase in erythroid precursor apoptosis of about 15-fold above our healthy controls. In searching for the causes of the variability in thalassemic erythroid precursor apoptosis, we discovered tight direct correlations between the relative and absolute extent of apoptosis and the extent of erythroid expansion as measured either by the absolute number of marrow erythroid precursors or by serum soluble transferrin receptor levels. These results could mean that the most extreme rates of erythroid proliferation lend themselves to cellular errors that turn on apoptotic programs. Alternatively, extreme rates of erythroid hyperplasia and apoptosis might be characteristic of more severely affected patients. Lastly, extreme erythroid hyperplasia could generate such numbers of apoptotic erythroid precursors that marrow macrophages are overwhelmed, leaving more apoptotic cells in the sample.
重型β地中海贫血的特征是红细胞生成无效，导致严重贫血和广泛的红系扩张。红细胞生成无效部分归因于地中海贫血红系前体细胞凋亡加速；然而，凋亡程度存在惊人的差异。为了理解这种差异以及一些接受异基因骨髓移植的患者对清髓方案耐药这一事实，我们尝试进行更定量的分析。我们研究了两组共44例患者，以及25名健康对照者和7例有溶血和/或红细胞生成无效的患者。通过两种流式细胞术方法，地中海贫血红系前体细胞凋亡率是正常水平的3至4倍。由于地中海贫血骨髓中的红系前体细胞比健康骨髓多5至6倍，这意味着红系前体细胞凋亡的绝对增加量比健康对照者高出约15倍。在寻找地中海贫血红系前体细胞凋亡差异的原因时，我们发现凋亡的相对和绝对程度与红系扩张程度之间存在紧密的直接相关性，红系扩张程度通过骨髓红系前体细胞的绝对数量或血清可溶性转铁蛋白受体水平来衡量。这些结果可能意味着最极端的红系增殖速率容易导致引发凋亡程序的细胞错误。或者，极端的红系增生和凋亡速率可能是病情更严重患者的特征。最后，极端的红系增生可能产生如此大量的凋亡红系前体细胞，以至于骨髓巨噬细胞不堪重负，使得样本中留下更多凋亡细胞。
