A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy
A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy
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DOI：
10.1182/blood-2005-08-3498
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发表时间：
2006-07-15
期刊：
影响因子：
20.3
通讯作者：
Kersey, John H.
中科院分区：
文献类型：
--
作者：
Chen, Weili;Li, Quanzhi;Kersey, John H.
2种最常见的人类MLL造血系统恶性肿瘤涉及AF 4或AF 9作为融合伴侣;每种都具有不同的生物学特性，但融合伴侣的作用尚不清楚。我们通过在胚胎干细胞中同源重组产生了MII-AF 4基因敲入（KI）小鼠，并将其与MII-AF 9 KI小鼠进行了比较。年轻的M11-AF 4小鼠具有淋巴和骨髓失调，表现为造血器官中淋巴和骨髓细胞增加。在体外，当在含有IL-7和Flt 3配体的培养基中生长时，来自年轻小鼠的骨髓细胞形成独特的混合前B淋巴细胞（B220（+）CD 19（+）CD 43（+）slgM（-），PAX 5（+），TdT（+），IgH重排）/髓样细胞（CD 11b/Mac 1（+），c-fms（+），溶菌酶（+））集落。MII-AF 4小鼠在延长的潜伏期后发生混合淋巴样/骨髓样增生和血液恶性肿瘤（最常见的是B细胞淋巴瘤）;恶性肿瘤的长潜伏期表明MII-AF 4诱导的淋巴样/骨髓样失调单独不足以产生恶性肿瘤。相比之下，年轻的MII-AF 9小鼠在体内和体外主要具有髓样失调，并发展成髓样恶性肿瘤。在MII-AF 4小鼠中，不同的混合淋巴/骨髓谱系失调的早期发作显示了AF 4和AF 9作为MLL融合基因中的伴侣的“指导性”和“非指导性”作用的证据。现在可以在我们的MII-AF 4模型中研究“指令”和次级合作突变的分子基础。
The 2 most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear. We produced MII-AF4 knock-in (KI) mice by homologous recombination in embryonic stem cells and compared them with MII-AF9 KI mice. Young M11-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoletic organs. In vitro, bone marrow cells from young mice formed unique mixed pro-B lymphold (B220(+)CD19(+)CD43(+)slgM(-), PAX5(+), TdT(+), IgH rearranged)/myeloid (CD11b/Mac1(+), c-fms(+), lysozyme(+)) colonies when grown in IL-7- and Flt3 ligand-containing media. Mixed lymphoid/myeloid hyperplasia and hematologic malignancies (most frequently B-cell lymphomas) developed in MII-AF4 mice after prolonged latency; long latency to malignancy indicates that MII-AF4-induced lymphold/myeloid deregulation alone is insufficient to produce malignancy. In contrast, young MII-AF9 mice had predominately myeloid deregulation in vivo and in vitro and developed myeloid malignancies. The early onset of distinct mixed lymphoid/myelold lineage deregulation in MII-AF4 mice shows evidence for both "instructive" and "noninstructive" roles for AF4 and AF9 as partners in MLL fusion genes. The molecular basis for "instruction" and secondary cooperating mutations can now be studied in our MII-AF4 model.