Moore Steven D P, Herrick Steven R, Ince Tan A, Kleinman Michael S, Dal Cin Paola, Morton Cynthia C, Quade Bradley J
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cancer Res. 2004 Aug 15;64(16):5570-7. doi: 10.1158/0008-5472.CAN-04-0050.
Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histones H1 and H5 and the PHD zinc fingers, the CH2CH zinc finger, or the CoA binding site, which is distinct from the breakpoints reported in AML. Mapping of the 17q21 breakpoint by fluorescence in situ hybridization within a specific region in three tumors revealed several positional candidates including GCN5L2, a gene with histone acetyltransferase activity similar to those fused to MORF in AML. Of note, two of three uterine leiomyomata were of the cellular subtype. Involvement of MORF in four uterine leiomyomata with chromosomal rearrangements involving 10q22 and 17q21 suggests a role for this histone acetyltransferase and altered chromatin regulation in uterine mesenchymal neoplasia.
良性子宫平滑肌瘤是育龄女性最常见的肿瘤。子宫平滑肌瘤中一个反复出现的染色体畸变是10q22重排。通过荧光原位杂交将4例检测的子宫平滑肌瘤中的10号染色体断点定位到MORF（单核细胞白血病锌指蛋白相关因子或MYST4）第三内含子内8.9至72.1 kb的区间。额外的Southern杂交实验证实断点位于第三内含子内，并将其中1例子宫平滑肌瘤的区间缩小至2.1 kb。MORF是组蛋白乙酰转移酶MYST家族的成员，此前已发现在某些类型的急性髓系白血病（AML）中发生重排。这是首次在另一种肿瘤类型中报道组蛋白乙酰转移酶被破坏的情况。子宫平滑肌瘤中的断点位于蛋白质的NH2末端部分，介于组蛋白H1和H5中发现的保守结构域与PHD锌指、CH2CH锌指或CoA结合位点之间，这与AML中报道的断点不同。通过荧光原位杂交将17q21断点定位到3个肿瘤中的特定区域，发现了几个位置候选基因，包括GCN5L2，一个具有与AML中与MORF融合的那些基因相似的组蛋白乙酰转移酶活性的基因。值得注意的是，3例子宫平滑肌瘤中有2例为细胞亚型。MORF参与4例涉及10q22和17q21染色体重排的子宫平滑肌瘤，提示该组蛋白乙酰转移酶以及染色质调控改变在子宫间叶肿瘤中发挥作用。
