Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias:: dominance of HOX dysregulation
Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias:: dominance of HOX dysregulation
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DOI：
10.1182/blood-2002-10-3221
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发表时间：
2003-07-01
期刊：
影响因子：
20.3
通讯作者：
Look, AT
中科院分区：
文献类型：
--
作者：
Ferrando, AA;Armstrong, SA;Look, AT
位于人类染色体11 q23上的MLL基因座的重排在婴儿和治疗相关的白血病中都很常见。MLL重排B前体急性淋巴细胞白血病（MLL B-ALL）的基因表达分析已将这些病例鉴定为白血病的独特亚型，其特征在于与淋巴和骨髓造血谱系相关的基因表达。在这里，我们表明，MLL融合也产生了一个独特的遗传亚型的T细胞系ALL（MLL T-ALL），其中白血病细胞的特点是在胸腺细胞分化的早期逮捕，与提示性的证据承诺的gammadelta谱系。有趣的是，与细胞增殖相关的多个基因（如PCNA、MYC、CDK 2和POLA）在MLL融合样本中相对于由其他T-ALL癌基因转化的样本下调（P <0.000 001，Fisher精确检验）。总的来说，MLL T-ALL病例始终显示主要HOX基因HOXA 9、HOXA 10和HOXC 6亚组以及MEIS 1 HOX辅助调节因子表达水平升高（P <0.008，单侧Wilcoxon检验），这种基因表达模式在MLL B-ALL中重复。然而，髓系基因的表达，以前报道的MLL B-ALL，没有确定在T-系的情况下，这种异常，表明髓系基因失调是由MLL融合蛋白介导的白血病转化。我们的研究结果暗示HOX基因家族成员的失调是嵌合MLL癌基因诱导白血病转化的主要机制。(C)2003年，美国血液学会。
Rearrangements of the MLL locus, located on human chromosome 11q23, are frequent in both infant and therapy-related leukemias..Gene expression analysis of MLL-rearranged B-precursor acute lymphoblastic leukemias (MLL B-ALLs) has identified these cases as a unique subtype of leukemia, characterized by the expression of genes associated with both lymphoid and myeloid hematopoietic lineages. Here we show that MLL fusions also generate a distinct genetic subtype of T-lineage ALL (MLL T-ALL), in which leukemic cells are characterized by an early arrest in thymocyte differentiation, with suggestive evidence of commitment to the gammadelta lineage. Interestingly, multiple genes linked to cell proliferation (eg, PCNA, MYC, CDK2, and POLA) were down-regulated in MLL-fusion samples, relative to those transformed by other T-ALL oncogenes (P < .000 001, Fisher exact test). Overall, MLL T-ALL cases consistently demonstrated increased levels of expression of a subset of major HOX genes-HOXA9, HOXA10, and HOXC6-and the MEIS1 HOX coregulator (P < .008, one-sided Wilcoxon test), a pattern of gene expression that was reiterated in MLL B-ALLS. However, expression of myeloid lineage genes, previously reported in MLL B-ALLs, was not identified in T-lineage cases with this abnormality, suggesting that myeloid gene dysregulation is dispensable in leukemic transformation mediated by MLL fusion proteins. Our findings implicate dysregulation of HOX gene family members as a dominant mechanism of leukemic transformation induced by chimeric MLL oncogenes. (C) 2003 by The American Society of Hematology.