Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice
Growth characteristics of acute myelogenous leukemia progenitors that initiate malignant hematopoiesis in nonobese diabetic/severe combined immunodeficient mice
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DOI：
10.1182/blood.v94.5.1761.417k23_1761_1772
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发表时间：
1999-09-01
期刊：
影响因子：
20.3
通讯作者：
Hogge, DE
中科院分区：
文献类型：
--
作者：
Ailles, LE;Gerhard, B;Hogge, DE
使用免疫缺陷小鼠，特别是非肥胖糖尿病/严重联合免疫缺陷（NOD/ SCID）株，允许检测非常原始的恶性祖细胞从急性髓细胞白血病（AML）患者。为了确定可以检测不同AML细胞植入的灵敏度和再现性，将来自新诊断的AML患者的61个不同样品注射到NOD/SCID小鼠中，这些样品代表各种细胞遗传学和法国-美国-英国（FAB）亚型。静脉注射10（7）个AML细胞后8周，小鼠骨髓中人细胞的平均百分比为13.3%，70%的样本显示出容易检测到的CD 45（+）细胞植入。具有与不良临床预后相关的细胞遗传学改变的AML样本倾向于比具有与良好预后相关的改变的AML样本移植到更高的水平。与来自其他亚型的细胞相比，具有FAB亚型M3和在较小程度上具有M2的细胞的移植更差（分别为P = 0.092和0.06）。每周三次腹腔注射人白细胞介素-3和Steel因子，持续4周，并没有提高AML细胞的植入水平。然而，在甲基纤维素测定中显示非依赖于精氨酸的集落生长或在恶性母细胞中表达生长因子mRNA的AML样品比在培养中依赖于细胞因子或不能表达细胞因子信息的AML样品获得显著更高水平的植入（分别为P <0.03和P <0.02）。在6例患者样本中，NOD/ SCID白血病起始细胞（NOD/SL-IC）的频率为0.7 - 45/10（7）个细胞，比相同样本中AML长期培养起始细胞（AML LTC-IC）的频率低200- 800倍。每个NOD/SL-IC将产生超过10（7）个白血病原始细胞以及许多AML-CFC和AML LTC-IC，在注射到小鼠后8周检测到。系列移植实验表明，NODI SL-IC能够在体内至少3至4周内维持其自身的数量。这些祖细胞自我更新的能力与其分化产生大量更成熟的祖细胞和白血病母细胞的潜力相结合，表明NOD/SL-IC测定鉴定了可能在人类患者中维持恶性克隆的白血病“干细胞”。该检测方法的进一步应用将促进AML干细胞生物学研究和新治疗策略的发展。(C)1999年，美国血液学会。
The use of immunodeficient mice, particularly of the nonobese diabetic/severe combined immunodeficient (NOD/ SCID) strain, has allowed detection of very primitive malignant progenitors from patients with acute myelogenous leukemia (AML). To define the sensitivity and reproducibility with which the engraftment of different AML cells can be detected, 61 different samples from patients with newly diagnosed AML representing a variety of cytogenetic and French-American-British (FAB) subtypes were injected into NOD/SCID mice. Eight weeks after intravenous injection of 10(7) AML cells, the average percent of human cells in mouse bone marrow was 13.3%, with 70% of samples showing easily detectable engraftment of CD45(+) cells. AML samples with cytogenetic changes associated with a poor clinical prognosis tended to engraft to higher levels than those with changes associated with a good prognosis. Cells;with FAB subtypes M3 and, to a lesser extent, M2, engrafted more poorly (P = .092 and .06, respectively) than those from other subtypes. Intraperitoneal injection of human interleukin-3 and Steel factor thrice weekly for 4 weeks did not enhance the levels of AML cell engraftment. However, AML samples that showed cytokine-independent colony growth in methyl-cellulose assay or expressed growth-factor mRNA in malignant blasts achieved significantly higher levels of engraftment than those which were cytokine dependent in culture or failed to express cytokine message (P < .03 and P < .02, respectively). In 6 patient samples, the frequency of NOD/ SCID leukemia-initiating cells (NOD/SL-IC) varied from 0.7 to 45 per 10(7) cells, which was 200- to 800-fold lower than the frequency of AML long-term culture-initiating cells (AML LTC-IC) in the same samples. Each NOD/SL-IC will produce more than 10(7) leukemic blasts as well as many AML-CFC and AML LTC-IC as detected 8 weeks postinjection into mice. Serial transplant experiments showed the ability of NODI SL-IC to maintain their own numbers over at least 3 to 4 weeks in vivo. The ability of these progenitors to self-renew combined with their potential to differentiate to produce large numbers of more mature progenitors and leukemic blasts suggests that the NOD/SL-IC assay identifies leukemic 'stem cells' that may maintain the malignant clone in human patients. The further use of this assay should facilitate studies of AML stem cell biology and the evolution of novel therapeutic strategies. (C) 1999 by The American Society of Hematology.