Role of Septin 6 in the lymphoid lineage and hematopoiesis

Septins, a family of GTP-binding proteins, belong to cytoskeletal proteins. They are able to form filaments and have several functions as diffusion barriers during cytokinesis and in steady state; they also act as scaffolds and define cell asymmetry/polarity. Furthermore, septin proteins regulate cell shape, which is crucial for cell motility and function. There is diverse data about the role of septin 6 in the hematopoietic system. While it is reported that septin 6 does not seem to play a role in normal hematopoiesis at steady state, the protein is found as a fusion partner of mixed-lineage leukemia (MLL) in infant acute myeloid leukemia that differentiates into the myeloid lineage. Furthermore septin 6 was shown, besides other septins, to be important for cell morphology and motility of T lymphocytes, which is disturbed upon loss of septin 6. We found that septin 6 shows pronounced filaments specifically in lymphoid primed multipotent progenitors (Lin-C-kit+Sca1+Flt3+CD34+) (LMPPs), which could not be observed to this extent in more primitive cells (Lin-C-kit+Sca1+Flt3-CD34+/-) or in myeloid committed precursors (Lin-C-kit+Sca1-). We thus hypothesize that septin 6 has a specific role in the commitment and differentiation of cells to the lymphoid lineage. Characterization of the hematopoietic system of septin 6 knockout (KO) mice at steady state showed a slight increase of B cells in peripheral blood and an increase of 17% in the bone marrow compared to wildtype (WT) mice. Cell frequencies in the stem cell compartment were not significantly different in KO and WT mice at steady state. Transplantation experiments are underway to investigate the functional impact of septin 6 loss in LT-HSCs as well as LMPPs. Further studies will shed light on the molecular pathways that depend on septin 6 in hematopoiesis.