Peng, XiaolanDong, MMa, LJia, X-EMao, JJin, CChen, YGao, LLiu, XMa, KWang, LDu, TJin, YHuang, QLi, KZon, LeonardLiu, TDeng, MZhou, YXi, XZhou, YiChen, S2018-04-122015Peng, X, M Dong, L Ma, X-E Jia, J Mao, C Jin, Y Chen, et al. 2015. “A Point Mutation of Zebrafish c-Cbl Gene in the Ring Finger Domain Produces a Phenotype Mimicking Human Myeloproliferative Disease.” Leukemia 29 (12) (June 24): 2355–2365. doi:10.1038/leu.2015.154.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:35642151Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs.Leukemia advance online publication, 14 July 2015; doi:10.1038/leu.2015.154.en-UShematopoietic stem/progenitor cellsc-cblmyeloproliferative neoplasms (MPN)flt3N-ethyl-N-nitrosourea (ENU) mutagenesis screeningJournal Article2015-06-11Xiaolan Peng1,*, Mei Dong2,*, Lie Ma5,1*, Xiao-E Jia2, Jianhua Mao1, Changbin Jin2, Yi Chen1, Lei Gao2, Xiaohui Liu1, Ke Ma2, Lei Wang2, Tingting Du1, Yi Jin1, Qiuhua Huang1, Keqin Li1, Leonard I. Zon3,4, Tingxi Liu1,2, Min Deng2, #, Yong Zhou2, #, Xiaodong Xi1, Yi Zhou3, #, Saijuan Chen1,#2018-04-1210.1038/leu.2015.154