德国弗赖堡大学医院１７日发表公报说，该院研究人员发现了导致幼年型粒—单核细胞白血病的可遗传性基因变异。这一成果有助于对各种白血病成因及疗法的研究。
幼年型粒—单核细胞白血病是一种罕见的恶性血癌，多发于幼儿。该院儿童与青少年医学中心的研究人员首先发现，在１５％患儿的血液中，一种名为ＣＢＬ的基因出现变异；他们随后又发现，所有患儿家长体内都有ＣＢＬ突变，其中５０％出现在家长的精子或卵子细胞中，另外５０％出现在身体的其他器官中。
研究人员说，由于许多患儿有语言学习障碍、发育不良、弱听和隐睾等症状，他们认为，ＣＢＬ基因的正常表达对众多器官的发育都非常重要。
研究人员表示，这一成果将有助于对各种白血病成因及其疗法的进一步研究。此外，导致患儿白细胞增多的信号传导问题也出现在其他一些癌症中，因此这一研究成果对提高癌症治疗水平具有普遍意义。
这一成果发表在最新一期《自然—基因学》上。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Genetics doi:10.1038/ng.641
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia
Charlotte M Niemeyer1,18, Michelle W Kang2,18, Danielle H Shin2,18, Ingrid Furlan1, Miriam Erlacher1, Nancy J Bunin3, Severa Bunda4, Jerry Z Finklestein5, Kathleen M Sakamoto6, Thomas A Gorr1, Parinda Mehta7, Irene Schmid8, Gabriele Kropshofer9, Selim Corbacioglu10, Peter J Lang11, Christoph Klein12, Paul-Gerhard Schlegel13, Andrea Heinzmann1, Michaela Schneider1, Jan Stary14, Marry M van den Heuvel-Eibrink15, Henrik Hasle16, Franco Locatelli17, Debbie Sakai2, Sophie Archambeault2, Leslie Chen2, Ryan C Russell4, Stephanie S Sybingco4, Michael Ohh4, Benjamin S Braun2, Christian Flotho1 & Mignon L Loh2
CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.
