CBFβ-SMMHC slows proliferation of primary murine and human myeloid progenitors
CBFβ-SMMHC slows proliferation of primary murine and human myeloid progenitors
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DOI：
10.1038/sj.leu.2403755
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发表时间：
2005-06-01
期刊：
影响因子：
11.4
通讯作者：
Friedman, AD
中科院分区：
文献类型：
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作者：
D'Costa, J;Chaudhuri, S;Friedman, AD
CBF beta-SMMHC 在 8% 的急性髓系白血病中表达，并抑制 AML1/RUNX1。在这项研究中，用表达 CBF beta-SMMHC 或两种突变变体的逆转录病毒或慢病毒载体转导小鼠骨髓或人 CD34(+) 细胞。相对于空载体转导的细胞，CBF beta-SMMHC 在液体培养中使小鼠或人骨髓细胞的增殖减少三到四倍，而载体转导的细胞积累了五倍，人类细胞积累了 20 倍。 CBF beta-SMMHC 减少了骨髓集落的形成，但不减少红细胞集落的两到四倍，并且表达 CBF beta-SMMHC 的骨髓集落的大小显着减小。然而，CBF beta-SMMHC 不会减缓向粒细胞或单核细胞的分化。 CBF beta-SMMHC（Delta 2 - 11）不结合 AML1，CBF beta-SMMHC（Delta ACD）也不会多聚化或有效结合辅阻遏物，从而减缓增殖或减少骨髓集落。 CBF beta-SMMHC 使 G1/S 比率增加 1.4 倍。 AML1具有与CBF beta-SMMHC相反的作用，在液体培养物中刺激小鼠骨髓祖细胞增殖2.0倍。因此，CBF beta-SMMHC 通过抑制 AML1 并依赖于其组装能力域的完整性，直接抑制正常骨髓祖细胞的增殖。这些发现支持开发针对 CBF beta-SMMHC 与 AML1 相互作用或通过其组装能力域进行多聚化的能力的治疗方法。
CBF beta- SMMHC is expressed in 8% of acute myeloid leukemias and inhibits AML1/ RUNX1. In this study, murine marrow or human CD34(+) cells were transduced with retroviral or lentiviral vectors expressing CBF beta-SMMHC or two mutant variants. CBF beta-SMMHC reduced murine or human myeloid cell proliferation three- to four- fold in liquid culture relative to empty vector-transduced cells, during a period when vector- transduced cells accumulated five- fold and human cells 20- fold. CBF beta-SMMHC decreased the formation of myeloid, but not erythroid, colonies two- to four- fold, and myeloid colonies expressing CBF beta-SMMHC were markedly reduced in size. However, CBF beta-SMMHC did not slow differentiation to granulocytes or monocytes. Neither CBF beta-SMMHC( Delta 2 - 11), which does not bind AML1, nor CBF beta-SMMHC( Delta ACD), which does not multimerize or efficiently bind corepressors, slowed proliferation or reduced myeloid colonies. CBF beta-SMMHC increased the G1/ S ratio 1.4- fold. AML1 had an effect opposite to CBF beta- SMMHC, stimulating proliferation of murine myeloid progenitors 2.0- fold in liquid culture. Thus, CBF beta- SMMHC directly inhibits the proliferation of normal myeloid progenitors via inhibition of AML1 and dependent upon the integrity of its assembly competence domain. These findings support the development of therapeutics that target the ability of CBF beta- SMMHC to interact with AML1 or to multimerize via its assembly competence domain.