Rujkijyanont Piya, Beyene Joseph, Wei Kuiru, Khan Fahad, Dror Yigal
Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology, Department of Paediatrics, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Br J Haematol. 2007 Jun;137(6):537-44. doi: 10.1111/j.1365-2141.2007.06608.x.
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder with cytopenia and a high propensity for myelodysplastic syndrome (MDS) and leukaemia, particularly acute myeloid leukaemia. The mechanism of leukaemogenesis in SDS is unknown. In accordance to the multi-hit theory of carcinogenesis, it is likely that several molecular and cellular hits occur before MDS/leukaemia become apparent. This study used oligonucleotide microarray to identify gene expression patterns, which were shown to be associated with leukaemogenesis, in marrow mononuclear cells of nine SDS patients without overt transformation compared to healthy controls. Among 154 known leukaemia-related genes, several oncogenes were found to be upregulated, including LARG, TAL1 and MLL, and of several tumour suppressor genes were downregulated, including DLEU1, RUNX1, FANCD2 and DKC1. Real time polymerase chain reaction confirmed statistically higher expression of LARG and TAL1 in SDS marrows. We conclude that SDS marrow mononuclear cells exhibit abnormal gene expression patterns, which might result in continuous stimulation favouring evolution or progression of malignant clones. Additional molecular and cytogenetic events are probably necessary for the malignant process to be irreversible and complete.
施瓦赫曼-戴蒙德综合征（SDS）是一种遗传性骨髓衰竭疾病，伴有血细胞减少，且极易发展为骨髓增生异常综合征（MDS）和白血病，尤其是急性髓系白血病。SDS中白血病发生的机制尚不清楚。根据癌症发生的多步骤理论，在MDS/白血病显现之前，可能发生了多个分子和细胞层面的改变。本研究使用寡核苷酸微阵列来鉴定与白血病发生相关的基因表达模式，将9例未发生明显转化的SDS患者的骨髓单个核细胞与健康对照进行比较。在154个已知的白血病相关基因中，发现几个癌基因上调，包括LARG、TAL1和MLL，几个抑癌基因下调，包括DLEU1、RUNX1、FANCD2和DKC1。实时聚合酶链反应证实SDS骨髓中LARG和TAL1的表达在统计学上更高。我们得出结论，SDS骨髓单个核细胞表现出异常的基因表达模式，这可能导致持续刺激，有利于恶性克隆的演变或进展。恶性过程要变得不可逆转并完全发展，可能还需要其他分子和细胞遗传学事件。
