Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm
Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm
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DOI：
10.1182/blood-2009-08-236596
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发表时间：
2010-04-08
期刊：
影响因子：
20.3
通讯作者：
Green, Anthony R.
中科院分区：
文献类型：
--
作者：
Beer, Philip A.;Delhommeau, Francois;Green, Anthony R.
急性髓性白血病（AML）可能发生在JAK 2阳性的骨髓增生性肿瘤（MPN）之后，尽管疾病演变的机制（通常涉及突变型JAK 2的丢失）仍然不清楚。我们研究了16例JAK 2突变型（16例中的7例）或JAK 2野生型（16例中的9例）AML患者接受JAK 2突变型MPN后的情况。原发性骨髓纤维化或骨髓纤维化转化发生在所有7种JAK 2突变型AML之前，但仅发生在9种JAK 2野生型AML中的1种之前（P = .001），这意味着JAK 2突变型AML发生在引起“骨髓纤维化”表型的突变之前。在所有野生型AML中，排除了有丝分裂重组、基因转换或缺失导致的JAK 2突变丢失。对其他突变的研究发现了RUNX 1、WT 1、TP 53、CBL、NRAS和TET 2的改变，JAK 2突变型和野生型白血病之间没有显著差异。在4例患者中，TP 53、CBL或TET 2突变存在于JAK 2野生型白血病原始细胞中，但不存在于JAK 2突变型MPN中。相比之下，在慢性期患者中，JAK 2或MPL中携带突变的克隆代表共享TET 2突变祖先克隆的后代。这些结果表明，不同的发病机制的基础转化为JAK 2野生型和JAK 2突变AML，表明TET 2突变可能存在于一个克隆不同于窝藏JAK 2突变，并强调克隆异质性的MPN。（血。2010; 115（14）：2891-2900）
Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a "myelofibrosis" phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion, or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL, or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic-phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs. (Blood. 2010; 115(14): 2891-2900)