Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
Blood. 2011 Jul 7;118(1):177-81. doi: 10.1182/blood-2010-12-327593. Epub 2011 May 11.
The JAK2 V617F mutation is present in the majority of patients with a myeloproliferative neoplasm (MPN) and is sufficient to recapitulate an MPN in murine models. However, the consequences of JAK2 mutations for myeloid differentiation are poorly understood. After systematic analyses of a large cohort of JAK2-mutated MPN patients, we demonstrate in vivo that JAK2 mutations do not alter hematopoietic stem and progenitor cell com-partment size or in vitro behavior but generate expansion of later myeloid differentiation compartments, where homozygous expression of the mutation confers an added proliferative advantage at the single-cell level. In addition, we demonstrate that these findings may be partially explained by the expression pattern of JAK2, which markedly increases on myeloid differentiation. Our findings have potential clinical relevance, as they predict that JAK2 inhibitors may control myeloproliferation, but may have limited efficacy in eradicating the leukemic stem cells that sustain the human MPN.
JAK2 V617F 突变存在于大多数骨髓增殖性肿瘤（MPN）患者中，并且足以在小鼠模型中重现 MPN。然而，JAK2 突变对髓系分化的影响知之甚少。在对一大群 JAK2 突变的 MPN 患者进行系统分析后，我们在体内证明 JAK2 突变不会改变造血干细胞和祖细胞池的大小或体外行为，但会产生后期髓系分化池的扩增，其中突变的纯合表达在单细胞水平赋予额外的增殖优势。此外，我们证明这些发现可能部分解释为 JAK2 的表达模式，该模式在髓系分化时显著增加。我们的研究结果具有潜在的临床意义，因为它们预测 JAK2 抑制剂可能控制骨髓增殖，但在根除维持人类 MPN 的白血病干细胞方面可能效果有限。
