Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis
Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis
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DOI：
10.1182/blood-2007-05-089003
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发表时间：
2007-11-15
期刊：
影响因子：
20.3
通讯作者：
Giraudier, Stephane
中科院分区：
文献类型：
--
作者：
Chaligne, Ronan;James, Chloe;Giraudier, Stephane
在某些类型的原始骨髓纤维化(PMF)患者的粒细胞中检测到MPL(W515L和W515K)突变。目前尚不清楚这一分子事件是否也存在于淋巴细胞中，因此可能存在于造血干细胞(HSC)水平。为此，我们对携带W515突变的PMF患者分离的成熟髓系和淋巴系细胞以及淋巴/髓系祖细胞进行了MPL基因分型。我们在粒细胞、单核细胞、血小板和自然杀伤(NK)细胞中都检测到MPL突变，但在T细胞中没有检测到突变。发现B/NK/髓系和/或NK/髓系CD34(+)、CD38(-)来源的克隆携带突变。在非肥胖糖尿病/严重联合免疫缺陷(NOD/SCID)小鼠移植后12周内，MPL W515 CD34(+)细胞的长期重建成功，表明iHSC中存在MPL W515突变。此外，这两个MPL突变在培养中诱导了自发的巨核细胞生长，对血小板生成素(TPO)的反应总体正常。相反，红系祖细胞仍然依赖EPO。这些结果表明，在PMF中，MPL W515L或K突变诱导了自发性巨核细胞(MK)分化，并出现在多能iHSCs中。
The MPL (W515L and W515K) mutations have been detected in granulocytes of patients suffering from certain types of primitive myelofibrosis (PMF). It is still unknown whether this molecular event is also present in lymphoid cells and therefore potentially at the hematopoletic stem cell (HSC) level. Toward this goal, we conducted MPL genotyping of mature myeloid and lymphoid cells and of lymphoid/ myeloid progenitors isolated from PMF patients carrying the W515 mutations. We detected both MPL mutations in granulocytes, monocytes, and platelets as well as natural killer (NK) cells but not in T cells. B/NK/myelold and/or NK/myeloid CD34(+)CD38(-)-derived clones were found to carry the mutations. Long-term reconstitution of MPL W515 CD34(+) cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice was successful for as long as 12 weeks after transplantation, indicating that MPL W515 mutations were present in IHSCs. More-over, the 2 MPL mutations induced a spontaneous megakaryocytic growth in culture with an overall normal response to thrombopoietin (TPO). In contrast, erythroid progenitors remained EPO dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation and occurs in a multipotent IHSCs.