Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms
Molecular mechanisms associated with leukemic transformation of MPL-mutant myeloproliferative neoplasms
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DOI：
10.3324/haematol.2010.029306
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发表时间：
2010-12-01
期刊：
影响因子：
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通讯作者：
Green, Anthony R.
中科院分区：
文献类型：
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作者：
Beer, Philip A.;Ortmann, Christina A.;Green, Anthony R.
血小板生成素受体MPL的体细胞激活突变发生在骨髓增生性肿瘤中，尽管实际上对它们在急性髓性白血病演变中的作用一无所知。在这项研究中，在新发急性髓性白血病中发现的MPL T487A突变在172例骨髓增生性肿瘤患者中未检测到。在既往有MPL W515L突变型骨髓增生性肿瘤的患者中，白血病转化伴随有MPL突变型白血病原始细胞，在既往无细胞减灭治疗的情况下可见，通常涉及有丝分裂重组导致的野生型MPL丢失。此外，白血病转化时祖细胞集落的克隆分析显示存在多个遗传上不同但具有不同TP53突变的造血相关克隆，这意味着突变体表型，并表明白血病转化可能是由不同造血克隆的平行扩增引起的。
Somatic activating mutations in MPL, the thrombopoietin receptor, occur in the myeloproliferative neoplasms, although virtually nothing is known about their role in evolution to acute myeloid leukemia. In this study, the MPL T487A mutation, identified in de novo acute myeloid leukemia, was not detected in 172 patients with a myeloproliferative neoplasm. In patients with a prior MPL W515L-mutant myeloproliferative neoplasm, leukemic transformation was accompanied by MPL-mutant leukemic blasts, was seen in the absence of prior cytoreductive therapy and often involved loss of wild-type MPL by mitotic recombination. Moreover, clonal analysis of progenitor colonies at the time of leukemic transformation revealed the presence of multiple genetically distinct but phylogenetically-related clones bearing different TP53 mutations, implying a mutator-phenotype and indicating that leukemic transformation may be preceded by the parallel expansion of diverse hematopoietic clones.