TIP110/p110^nrb/SART3/p110 regulation of hematopoiesis through CMYC

Intracellular factors are involved in and essential for hematopoiesis. HIV-1 Tat-interacting protein of 110 kDa (TIP110; p110^nrb/SART3/p110) is an RNA-binding nuclear protein implicated in the regulation of HIV-1 gene and host gene transcription, pre-mRNA splicing, and cancer immunology. In the present study, we demonstrate a role for TIP110 in the regulation of hematopoiesis. TIP110 was expressed in human CD34⁺ cells and decreased with differentiation of CD34⁺ cells. TIP110 mRNA was also expressed in phenotyped mouse marrow hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Using TIP110 transgenic (TIP110 ^TG) and haploinsufficient (TIP110^+/-) mice, we found that increased TIP110 expression enhanced HPC numbers, survival, and cell cycling, whereas decreased TIP110 expression had the opposite effects. Moreover, TIP110^+/- bone marrow HPCs responded more effectively, and TIP110^TG HPCs less effectively, than those of wild-type control mice to recovery from the cell-cycle-active drug 5-fluorouracil (5-FU). Unexplained sex differences were noted in HSC competitive repopulating ability, but not HPC numbers, in TIP110^TG mice. Intracellularly, TIP110 regulated CMYC and GATA2 expression at the transcriptional level, and TIP110 and CMYC reciprocally regulated the expression of each other. These results demonstrate a role for TIP110 in the regulation of hematopoiesis, effects that are likely linked to TIP110 regulation of CMYC.