Cell Research (2011) 21: 1370-1373. doi: 10.1038/cr. 2011.115; published online 19 July 2011 type mice appeared normal. Pathological examination demonstrated that the DOT1L2lox/1ox/Cre-ER mice display severe anemia in internal organs such as the liver (Figure 1A). In addition, brain hemorrhaging is observed upon loss of DOT1L in the DOT1L2lox/1ox/Cre-ER mice, which is absent in the DOT1Lwt/wt/Cre-ER controls (Figure 1B). Consistent with these observations, a general hypocellularity in the bone marrow of DOT1L2lox/1ox/Cre-ER mice was also observed when compared to wild-type controls (Figure 1C).

To determine the effect of DOT1L depletion in hematopoietic lineage development, FACS analyses were performed on bone marrow cells isolated from the experimental mice (Supplementary information, Data S1). The results demonstrated that the percentages of multiple progenitors including CMP (common myeloid progenitors), GMP (granulocyte/monocyte progenitors), and MEP (megakaryocyte/erythrocyte progenitors) are reduced significantly in DOT1L2lox/1ox/Cre-ER mice compared with the wild-type control (Figure 1D, Supplementary information, Figure S2). Consistently, terminally differentiated myeloid lineage cells (Gr-1+ or Mac-1+) are also significantly reduced upon DOT1L deletion (Figure 1E, Supplementary information, Figure S2). Collectively, these data indicate that DOT1L is critical in maintaining normal adult hematopoiesis and that depletion of DOT1L leads to bone marrow failure. To determine whether Dot1L deletion-induced bone marrow failure observed above is caused by autonomous defects of hematopoietic cells, we performed bone marrow transplantation in which the DOT1L2lox/1ox/Cre-ER or DOT1Lwt/wt/Cre-ER donor cells were transplanted into congenic recipient mice (Supplementary information, Data S1). Four weeks after bone marrow reconstitution, TAM was administrated for 2 weeks to delete DOT1L in DOT1L2lox/1ox/Cre-ER donor cells. Two weeks after the last TAM injection, total bone marrow cells were isolated and counted. Compared to mice transplanted with wildtype donor cells, total bone marrow cells in the recipient mice transplanted with DOT1L2lox/1ox/Cre-ER cells are significantly reduced (Figure 1F). This result suggests