Zhao, ZhigangChen, LiDawlaty, Meelad M.Pan, FengWeeks, OpheliaZhou, YuanCao, ZengShi, HuiWang, JiapengLin, LiChen, ShiYuan, WeipingQin, ZhaohuiNi, HongyuNimer, Stephen D.Yang, Feng-ChunJaenisch, RudolfJin, PengXu, Mingjiang2016-03-292016-03-292015-11-24Zhao, Z., Chen, L., Dawlaty, M. M., Pan, F., Weeks, O., Zhou, Y., … Xu, M. (2015). Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. Cell Reports, 13(8), 1692–1704. http://doi.org/10.1016/j.celrep.2015.10.0372211-1247https://hdl.handle.net/1805/9085TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.en-USCC-BY-NC-NDTet1Tet2micemalignancieshematologyArticle