Transcription factor Tcf15 regulates lymphoid fate selection in hematopoietic system 4061

Description Expression of lymphoid genes has been shown to be uniquely antagonistic to hematopoietic stem cell (HSC) maintenance and function. The transcription factor Tcf15 was recently shown to be indispensable to HSC maintenance and function in the transplant setting, conferring long term HSC regenerative potential. Because HSC maintenance and function is so closely linked to regulation of lymphoid potential, we hypothesized that Tcf15 manipulation could alter T and B lymphoid fate selection. To examine whether Tcf15 could alter T and B fate selection, we first generated a Tcf15 overexpression (OE) mouse model, Col1a1TetOTcf15/TetOTcf15 R26M2rtTA/M2rtTA (TetO-Tcf15). TetO-Tcf15 mice showed a dramatic reduction in bone marrow (BM) B220+ cells and thymic CD4+CD8+ cells, as early as 10 days on dox. These results were recapitulated with TetO-Tcf15 BM transplantation, revealing cell autonomous regulation. Tcf15 OE also significantly decreased the frequencies of lymphoid biased BM progenitors, MPP4 and CLP. We next sought to identify the cellular mechanisms by which Tcf15 OE inhibits T and B fate selection. While TetO-Tcf15 MPP4s differentiated normally in vitro, on OP9 or OP9-Dll4, dox treated TetO-Tcf15 MPP4s failed to generate B or T cells. Initial scRNA sequence analysis has revealed that Tcf15 OE attenuates expression of DNTT, an enzyme critical to lymphoid development. Our data suggests that Tcf15 expression may repress regulatory networks that promote T and B lymphoid fate selection. Funding Sources K99/R00-MOSAIC (Aug 2024-July 2029) ASH Minority Hematology Fellow Award, American Society of Hematology (June 2022-June 2024) T32 Organ Design and Engineering Program Postdoctoral Training Grant (ODET), Brigham and Women’s Hospital, Harvard Medical School (June 2020-June 2021) Topic Categories Hematopoiesis and Immune System Development (HEM)