Transcription regulation in hematopoiesis

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Project Summary (Project 2) Cellular therapy, including hematopoietic stem/progenitor cell (HSPC) transplant, is a critical part of transfusion medicine practice. Umbilical cord blood can be an excellent alternative HSPC donor source; however its use is severely constrained by the limited HSPC numbers in one single cord blood unit. Despite our progress in understanding the molecular factors that support the self-renewal and differentiation of the hematopoietic system in vivo, less is known on how to modulate the factors that govern the self-renewal of HSPCs ex vivo. Unlike in the case of embryonic stem (ES) cells, expansion of HSPC in culture in general is at the expense of “stemness”. We hypothesize that the HSPC fate is governed by key transcription factors, which are down-regulated during HSPC ex vivo expansion. Transcription factors maintain the HSPC identity by bookmarking the epigenetic memories during cell division. Identifying these transcription factor(s) is critical for the development of ex vivo HSPC expansion technology. ES cell gene SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of ES cell properties. SALL4 is also a key factor in regulating human normal hematopoiesis, and can be used to expand cord blood HSPC population. The mechanism(s) of SALL4 in normal hematopoiesis, at least in part, is through its transcription activation domain and its interaction with the MLL epigenetic complex. Based on our preliminary studies, we propose the SALL4 transcription activation function is important for CD34+ HSPC expansion, and discovery of novel pharmacological tools to enhance its transcription activation property could potentially lead to new HSPC expansion technology. We have proposed the following specific aims: Specific Aim I: Characterize the functional role(s) of SALL4 transcription activation domain in HSPC expansion. Specific Aim II: Determine the molecular mechanism of SALL4 transcription activation domain in HSPC expansion. Specific Aim III: Screen and identify small molecule compounds to enhance SALL4 mediated HSPC expansion. Our proposed experiments, once completed, not only can offer us insights on HSPC biology, but also provide us with novel small molecule drugs for the purpose of HSPC expansion.