Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Blood. 2011 Jul 7;118(1):167-76. doi: 10.1182/blood-2011-01-331678. Epub 2011 Apr 29.
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.
费城染色体阴性骨髓增殖性肿瘤（MPN）是一种克隆性髓系疾病，其特征是终末分化细胞的过度生成。该疾病的病程通常是慢性的，但有些患者会出现疾病进展（继发性骨髓纤维化或加速期）和/或白血病转化。我们使用高分辨率单核苷酸多态性微阵列分析了 408 例 MPN 样本中的染色体异常，以鉴定与疾病相关的体细胞病变。在 408 例样本中，37.5%为野生型核型，62.5%至少存在 1 种染色体异常。我们鉴定出 25 种反复出现的异常，这些异常在 3 个或更多样本中均有发现。染色体病变数量的增加与患者年龄以及疾病进展和白血病转化显著相关，但与 MPN 亚型、Janus 激酶 2（JAK2）突变状态或疾病持续时间无关。染色体 1q 和 9p 的异常与继发性骨髓纤维化或加速期的疾病进展呈正相关。染色体 1q、7q、5q、6p、7p、19q、22q 和 3q 的改变与骨髓增生异常后急性髓系白血病呈正相关。我们将常见的受影响区域映射到染色体 3p（叉头框 P1 [FOXP1]）、4q（四联体基因家族成员 2 [TET2]）、7p（IKAROS 家族锌指 1 [IKZF1]）、7q（剪切样同源盒 1 [CUX1]）、12p（ets 变体 6 [ETV6]）和 21q（ runt 相关转录因子 1 [RUNX1]）上的单个靶基因。我们的数据提供了对 MPN 遗传复杂性的深入了解，并暗示了新的基因参与了疾病的进展。
