McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
Blood. 2011 Jul 14;118(2):368-79. doi: 10.1182/blood-2010-12-326058. Epub 2011 May 17.
Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. Here, we use a hypomorphic oncogenic Nras allele and a normal oncogenic Nras allele (Nras G12D(hypo) and Nras G12D, respectively) to create a gene dose gradient ranging from 25% to 200% of endogenous Nras G12D/+. Mice expressing Nras G12D(hypo)/G12D(hypo) develop normally and are tumor-free, whereas early embryonic expression of Nras G12D/+ is lethal. Somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to hyperactivation of ERK, excessive proliferation of myeloid progenitors, and consequently an acute myeloproliferative disease. Using a bone marrow transplant model, we previously showed that ∼ 95% of animals receiving Nras G12D/+ bone marrow cells develop chronic myelomonocytic leukemia (CMML), while ∼ 8% of recipients develop acute T-cell lymphoblastic leukemia/lymphoma [TALL] (TALL-het). Here we demonstrate that 100% of recipients transplanted with Nras G12D/G12D bone marrow cells develop TALL (TALL-homo). Although both TALL-het and -homo tumors acquire Notch1 mutations and are sensitive to a γ-secretase inhibitor, endogenous Nras G12D/+ signaling promotes TALL through distinct genetic mechanism(s) from Nras G12D/G12D. Our data indicate that the tumor transformation potential of endogenous oncogenic Nras is both dose- and cell type-dependent.
单等位基因和双等位基因致癌性 NRAS 突变都在人类白血病中被发现，这表明致癌性 NRAS 在白血病发生中具有剂量依赖性作用。在这里，我们使用一种低功能致癌性 Nras 等位基因和一种正常的致癌性 Nras 等位基因（分别为 Nras G12D(hypo) 和 Nras G12D），创建了一个从 25%到 200%内源性 Nras G12D/+的基因剂量梯度。表达 Nras G12D(hypo)/G12D(hypo)的小鼠正常发育且无肿瘤，而早期胚胎表达 Nras G12D/+则是致命的。体细胞表达 Nras G12D/G12D 但不表达 Nras G12D/+会导致 ERK 的过度激活、髓系祖细胞的过度增殖，进而导致急性髓系增殖性疾病。使用骨髓移植模型，我们之前表明，接受 Nras G12D/+骨髓细胞移植的动物中约有 95%会发展为慢性骨髓单核细胞白血病（CMML），而约 8%的受体会发展为急性 T 细胞淋巴母细胞白血病/淋巴瘤[TALL]（TALL-het）。在这里，我们证明了接受 Nras G12D/G12D 骨髓细胞移植的动物 100%会发展为 TALL（TALL-homo）。尽管 TALL-het 和 -homo 肿瘤都获得了 Notch1 突变并对 γ-分泌酶抑制剂敏感，但内源性 Nras G12D/+信号通过与 Nras G12D/G12D 不同的遗传机制促进 TALL 的发生。我们的数据表明，内源性致癌性 Nras 的肿瘤转化潜能既依赖于剂量又依赖于细胞类型。
