Ramshaw Hayley S, Bardy Peter G, Lee Melissa A, Lopez Angel F
Cytokine Receptor Laboratory, Division of Human Immunology, IMVS, Adelaide, South Australia, Australia.
Exp Hematol. 2002 Oct;30(10):1124-31. doi: 10.1016/s0301-472x(02)00903-7.
Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease with no effective treatments or cure. Several factors have been implicated in its pathogenesis. In the current study, we studied the dependence of CMML on granulocyte-macrophage colony-stimulating factor (GM-CSF).
We used in vitro colony assays in methylcellulose where CMML cells were tested in the presence or absence of the specific GM-CSF antagonist E21R. We also developed an in vivo model in which CMML cells were tested for their ability to engraft into immunodeficient mice transgenic for human GM-CSF.
Bone marrow cells from seven of seven patients with CMML formed spontaneous colonies that were sensitive to E21R treatment, with reduction in colony growth by up to 92%. E21R also inhibited colony formation by CMML patient cells stimulated by exogenously added GM-CSF but not interleukin-3. In in vivo experiments we observed engraftment of CMML cells (but not normal cells) in immunodeficient mice transgenic for human GM-CSF. None engrafted in nontransgenic mice. Cell dose escalation showed that the optimal number was 0.5 to 1 x 10(8) peripheral blood mononuclear cells per mouse, which is equivalent to an infusion of 0.2 to 3.6 x 10(6) CD34(+) cells. Time course experiments showed that maximal engraftment occurred 6 weeks after injection.
These results demonstrate that in some CMML patients, GM-CSF produced by either autocrine or paracrine mechanisms is a major growth determinant. The results suggest that therapies directed at blocking this cytokine could control the growth of some CMML patients in vivo.
慢性粒单核细胞白血病（CMML）是一种异质性疾病，尚无有效的治疗方法或治愈手段。其发病机制涉及多个因素。在本研究中，我们研究了CMML对粒细胞-巨噬细胞集落刺激因子（GM-CSF）的依赖性。
我们使用甲基纤维素中的体外集落测定法，在有或没有特异性GM-CSF拮抗剂E21R的情况下对CMML细胞进行检测。我们还建立了一种体内模型，在该模型中检测CMML细胞植入人GM-CSF转基因免疫缺陷小鼠的能力。
7例CMML患者的骨髓细胞均形成了对E21R治疗敏感的自发集落，集落生长减少高达92%。E21R还抑制了外源性添加GM-CSF刺激的CMML患者细胞的集落形成，但不抑制白细胞介素-3刺激的集落形成。在体内实验中，我们观察到CMML细胞（而非正常细胞）植入了人GM-CSF转基因免疫缺陷小鼠。在非转基因小鼠中均未植入。细胞剂量递增显示，最佳数量为每只小鼠0.5至1×10⁸外周血单个核细胞，这相当于输注0.2至3.6×10⁶个CD34⁺细胞。时间进程实验显示，最大植入发生在注射后6周。
这些结果表明，在一些CMML患者中，通过自分泌或旁分泌机制产生的GM-CSF是主要的生长决定因素。结果表明，针对阻断这种细胞因子的疗法可以在体内控制一些CMML患者的生长。
