Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
Haematologica. 2012 Feb;97(2):219-26. doi: 10.3324/haematol.2010.035006. Epub 2011 Oct 11.
CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.
We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.
As assessed by flow cytometry, stem cell-enriched CD34(+)/CD38(-)/CD123(+) leukemic cells expressed significantly higher levels of CD33 compared to normal CD34(+)/CD38(-) stem cells. Moreover, highly enriched leukemic CD34(+)/CD38(-) cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34(+)/CD38(-) cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.
CD33 is expressed abundantly on immature CD34(+)/CD38(-) stem cells and may serve as a stem cell target in chronic myeloid leukemia.
CD33 是急性髓系白血病中一种众所周知的干细胞靶点。然而，迄今为止，人们对慢性白血病中白血病干细胞上 CD33 的表达知之甚少。
我们通过多色流式细胞术和定量聚合酶链反应分析了慢性髓性白血病中白血病祖细胞上 CD33 的表达。此外，还研究了一种针对 CD33 的药物 gemtuzumab/ozogamicin 的作用。
流式细胞术评估结果显示，与正常 CD34(+)/CD38(-) 干细胞相比，富含干细胞的 CD34(+)/CD38(-)/CD123(+) 白血病细胞表达 CD33 的水平显著更高。此外，高度富集的白血病 CD34(+)/CD38(-) 细胞（纯度>98%）显示 CD33mRNA 的水平更高。在慢性期患者中，CD33 始终在大多数或所有干细胞上表达，而在疾病加速或急变期，干细胞上 CD33 的水平因供体而异。MDR1 抗原，据称与对 ozogamicin 的耐药性有关，在白血病 CD34(+)/CD38(-) 细胞上不可检测。相应地，在所有测试的患者中，gemtuzumab/ozogamicin 对白血病祖细胞产生了生长抑制作用。gemtuzumab/ozogamicin 的作用呈剂量依赖性，在低浓度下发生，并伴有悬浮培养中的细胞凋亡。此外，该药物被发现可抑制集落测定和长期培养起始细胞测定中的白血病细胞生长。最后，发现 gemtuzumab/ozogamicin 与 nilotinib 和 bosutinib 协同作用，可诱导白血病细胞生长抑制。
CD33 在不成熟的 CD34(+)/CD38(-) 干细胞上表达丰富，可作为慢性髓性白血病中的干细胞靶点。
