Wickenhauser C
Zentrum für Pathologie, Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924 Köln, Germany.
Pathologe. 2002 Nov;23(6):457-64. doi: 10.1007/s00292-002-0576-7. Epub 2002 Oct 8.
Pluripotent hematopoietic stem cells have been defined as cells with extensive self-renewal capacity and lympho-hematopoietic differentiation potential. Clonal selection of a stem cell as a first step in the progression to neoplasia can be achieved by an alteration of this self-renewal potency. Our current understanding of the pathogenesis of the myeloproliferative disorders including acute myeloid leukemias, chronic myeloproliferative disorders (CMPD) and myelodysplastic syndromes (MDS), is based on the assumption that they represent a clonal disorder resulting from transformation of a hematopoietic stem cell. However, when performing methods for determining X-chromosome inactivation in female patients as a clonality marker, a significant minority of the patients with Philadelphia chromosome negative (Ph(-)) CMPD and MDS exhibit polyclonal proliferation. The implications of these results are not yet clarified and the lack of a proven target cell impairs the understanding of the underlying molecular defect. In this context, altered response to cytokine stimulation in vitro provides indirect information concerning molecular dysregulation. A subset of patients with MPD present with translocations that facilitate molecular investigation and clonality proof. They nearly always result in rearrangements of at least one transcription factor gene. Most of these fusion genes are constitutively active, sending out continuous proliferative and antiapoptotic signals or activate an overlapping set of signalling pathways. The classical example for a balanced translocation is the t(9;22) bcr-abl aberration in chronic myelogeneous leukemia. Many other karyotypic abnormalities have also been associated with CMPD and MDS and involve deletions of chromosomes 20q, 13q, 1q, 7q and 5q as well as trisomy of 8 and 9. Our increased understanding of the hematopoietic stem cell compartment and the molecular basis of regulation of its self-renewal and differentiation bears a direct impact on our understanding of leukemia evolution and progression.
多能造血干细胞被定义为具有广泛自我更新能力和淋巴细胞造血分化潜能的细胞。干细胞的克隆选择作为肿瘤形成过程中的第一步，可以通过改变这种自我更新能力来实现。我们目前对包括急性髓系白血病、慢性髓系增殖性疾病（CMPD）和骨髓增生异常综合征（MDS）在内的髓系增殖性疾病发病机制的理解，是基于它们代表一种由造血干细胞转化导致的克隆性疾病这一假设。然而，在对女性患者进行X染色体失活检测以作为克隆性标记的方法时，相当一部分费城染色体阴性（Ph(-)）的CMPD和MDS患者表现出多克隆增殖。这些结果的意义尚未阐明，并且缺乏经过验证的靶细胞妨碍了对潜在分子缺陷的理解。在这种情况下，体外对细胞因子刺激的反应改变提供了有关分子失调的间接信息。一部分MPD患者存在易位，这有助于进行分子研究和克隆性验证。它们几乎总是导致至少一个转录因子基因的重排。这些融合基因中的大多数是组成性激活的，发出持续的增殖和抗凋亡信号，或激活一组重叠的信号通路。平衡易位的经典例子是慢性髓性白血病中的t(9;22) bcr-abl畸变。许多其他染色体核型异常也与CMPD和MDS相关，包括20q、13q、1q、7q和5q染色体的缺失以及8号和9号染色体三体。我们对造血干细胞区室及其自我更新和分化调控分子基础的进一步理解，对我们理解白血病的演变和进展产生了直接影响。
