Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, 48109, USA.
Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, 48109, USA.
Am J Hematol. 2017 Jun;92(6):555-561. doi: 10.1002/ajh.24728. Epub 2017 May 2.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera, or myelofibrosis or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent. In an effort to characterize the underlying genetic events that might contribute to the appearance of more than one MPN in a patient, we studied neoplastic cells from patients with dual MPNs by next-generation sequencing. We observed that most patients with two MPNs harbored mutations in genes known to contribute to clonal hematopoiesis through altered epigenetic regulation such as TET2, ASXL1/2, SRSF2, and IDH2 at varying frequencies (1%-47%). In addition, we found that some patients also harbored oncogenic mutations in N/KRAS, TP53, BRAF, EZH2, and GNAS at low frequencies, which probably represent clonal evolution. These findings support the hypothesis that hematopoietic cells from MPN patients harbor multiple genetic aberrations, some of which can contribute to clonal dominance. Acquiring mutations in JAK2/CALR/MPL or the BCR-ABL translocation probably drive the oncogenic phenotype towards a specific MPN. Further, we propose that the acquisition of BCR-ABL in these patients is frequently a secondary event resulting from an unstable genome.
骨髓增殖性肿瘤（MPN）是克隆性造血干细胞（HSC）疾病，可以基于遗传、临床和表型特征进行分类。在 MPN 患者中，JAK2 突变和 BCR-ABL 易位等遗传病变通常是相互排斥的，分别导致特发性血小板增多症、真性红细胞增多症或骨髓纤维化或慢性髓性白血病。然而，已经报道了这些遗传异常在同一患者中的共存。这些异常是否发生在同一干细胞或不同细胞中尚不清楚，但 HSCs 中的不稳定基因组似乎是共同的前体。为了描述可能导致同一患者出现多种 MPN 的潜在遗传事件，我们通过下一代测序研究了双重 MPN 患者的肿瘤细胞。我们观察到，大多数患有两种 MPN 的患者携带已知通过改变表观遗传调节（如 TET2、ASXL1/2、SRSF2 和 IDH2）导致克隆性造血的基因中的突变，其频率在 1%-47%之间不等。此外，我们还发现一些患者还携带低频率的 N/KRAS、TP53、BRAF、EZH2 和 GNAS 致癌突变，这可能代表克隆进化。这些发现支持这样的假说，即 MPN 患者的造血细胞存在多种遗传异常，其中一些可能有助于克隆优势。获得 JAK2/CALR/MPL 或 BCR-ABL 易位的突变可能会使致癌表型向特定的 MPN 发展。此外，我们提出，这些患者中 BCR-ABL 的获得通常是不稳定基因组导致的继发事件。
