Zeisig Bernd B, Milne Tom, García-Cuéllar María-Paz, Schreiner Silke, Martin Mary-Ellen, Fuchs Uta, Borkhardt Arndt, Chanda Sumit K, Walker John, Soden Richard, Hess Jay L, Slany Robert K
Department of Genetics, University Erlangen, Staudtstrasse 5, 91058 Erlangen, Germany.
Mol Cell Biol. 2004 Jan;24(2):617-28. doi: 10.1128/MCB.24.2.617-628.2004.
MLL fusion proteins are oncogenic transcription factors that are associated with aggressive lymphoid and myeloid leukemias. We constructed an inducible MLL fusion, MLL-ENL-ERtm, that rendered the transcriptional and transforming properties of MLL-ENL strictly dependent on the presence of 4-hydroxy-tamoxifen. MLL-ENL-ERtm-immortalized hematopoietic cells required 4-hydroxy-tamoxifen for continuous growth and differentiated terminally upon tamoxifen withdrawal. Microarray analysis performed on these conditionally transformed cells revealed Hoxa9 and Hoxa7 as well as the Hox coregulators Meis1 and Pbx3 among the targets upregulated by MLL-ENL-ERtm. Overexpression of the Hox repressor Bmi-1 inhibited the growth-transforming activity of MLL-ENL. Moreover, the enforced expression of Hoxa9 in combination with Meis1 was sufficient to substitute for MLL-ENL-ERtm function and to maintain a state of continuous proliferation and differentiation arrest. These results suggest that MLL fusion proteins impose a reversible block on myeloid differentiation through aberrant activation of a limited set of homeobox genes and Hox coregulators that are consistently expressed in MLL-associated leukemias.
MLL融合蛋白是致癌转录因子，与侵袭性淋巴细胞白血病和髓细胞白血病相关。我们构建了一种可诱导的MLL融合蛋白MLL-ENL-ERtm，其使MLL-ENL的转录和转化特性严格依赖于4-羟基他莫昔芬的存在。MLL-ENL-ERtm永生化造血细胞需要4-羟基他莫昔芬才能持续生长，并在撤去他莫昔芬后终末分化。对这些条件性转化细胞进行的微阵列分析显示，Hoxa9和Hoxa7以及Hox共调节因子Meis1和Pbx3是MLL-ENL-ERtm上调的靶标。Hox阻遏物Bmi-1的过表达抑制了MLL-ENL的生长转化活性。此外，Hoxa9与Meis1的强制表达足以替代MLL-ENL-ERtm的功能，并维持持续增殖和分化停滞状态。这些结果表明，MLL融合蛋白通过异常激活一组在MLL相关白血病中持续表达的有限同源框基因和Hox共调节因子，对髓系分化施加可逆阻滞。
