Department of Haematology, Cambridge Institute for Medical Research, Cambridge, UK.
Blood. 2010 Apr 8;115(14):2891-900. doi: 10.1182/blood-2009-08-236596. Epub 2009 Dec 11.
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.
急性髓系白血病（AML）可能继发于 JAK2 阳性骨髓增殖性肿瘤（MPN），尽管疾病演变的机制，通常涉及突变 JAK2 的丧失，仍不清楚。我们研究了 16 例 JAK2 突变（16 例中的 7 例）或 JAK2 野生型（16 例中的 9 例）AML 患者，这些患者继发于 JAK2 突变的 MPN。原发性骨髓纤维化或骨髓纤维化转化先于所有 7 例 JAK2 突变型，但仅 1 例 JAK2 野生型 AML（P =.001），这意味着 JAK2 突变型 AML 之前存在导致“骨髓纤维化”表型的突变。在所有野生型 AML 中，通过有丝分裂重组、基因转换或缺失排除了 JAK2 突变的丢失。在 4 例患者中，RUNX1、WT1、TP53、CBL、NRAS 和 TET2 的改变被发现，JAK2 突变型和野生型白血病之间没有显著差异。在 4 例患者中，TP53、CBL 或 TET2 的突变存在于 JAK2 野生型白血病中，但不存在于 JAK2 突变的 MPN 中。相比之下，在慢性期患者中，JAK2 或 MPL 突变的克隆代表了共享 TET2 突变祖细胞克隆的后代。这些结果表明，向 JAK2 野生型和 JAK2 突变型 AML 的转化有不同的发病机制，表明 TET2 突变可能存在于与 JAK2 突变不同的克隆中，并强调了 MPN 的克隆异质性。
