Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner

Abstract

Sall4 is a transcription factor that exists in two splice isoforms – Sall4a and Sall4b – and regulates transcription in embryonic stem cells, hematopoiesis and acute myeloid leukemia. Constitutive overexpression of Sall4 in mice induces acute myeloid leukemia. Interestingly, a potential benefit of using Sall4 to facilitate ex vivo hematopoietic stem cell expansion has been proposed. However, distinct roles for how Sall4 contributes to normal versus malignant processes remain undefined. Here we show that Sall4b is the predominant isoform in murine hematopoietic stem cells and progenitors. Overexpression of either Sall4 isoform in HSCs or progenitors impairs hematopoietic colony formation and expansion in vitro. Lineage negative bone marrow overexpressing Sall4b fails to engraft and reconstitute hematopoiesis when transplanted. We found that both Sall4a and Sall4b overexpression impair hematopoiesis in part through dose-dependent repression of Bmi1. Additionally we have identified the following potential novel Sall4 target genes in hematopoiesis: Arid5b (Sall4a and Sall4b), Ezh2 and Klf2 (Sall4a). Lastly, we found that Sall4 expression is variable in acute myeloid leukemia, ranging from no expression to levels comparable to embryonic stem cells. These results show that Sall4 isoforms contribute to only a subset of acute myeloid leukemia and that overexpression of Sall4 isoforms impairs hematopoiesis through repression of Bmi1. Together these data demonstrate the sensitivity of hematopoiesis to appropriately balanced Sall4 expression, highlighting the importance of regulating this dynamic in potential therapeutic applications such as ex vivo stem cell expansion.

Dynamic Protein Interactions of the Polycomb Repressive Complex 2 during Differentiation of Pluripotent Cells

“…Another protein found to favor interaction with PRC2 in undifferentiated NT2 cells is SALL4, a zinc finger transcription factor that is essential for ES cell formation (43). It is a regulator of the PRC1 protein BMI1 in hematopoietic cells (44,45). To our knowledge, our data is the first report of a physical interaction between SALL4 and a PRC2 protein.…”

Human haematopoietic stem/progenitor cells express several functional sex hormone receptors

“…Accordingly, human and murine germline‐derived teratocarcinoma cell lines as well as ovarian cancer cell lines respond to EPO by chemotaxis, increased adhesion and phosphorylation of MAPKp42/44 and AKT . Finally, the transcription factor Sall4 has been reported to play an important role in both haematopoiesis and germline development .…”

Optimizing autologous cell grafts to improve stem cell gene therapy

“…In one of the few studies attempting to expand mobilized PB rather than UCB, SALL4-transduced human CD34(+)/CD38(-) and CD34(+)/CD38(+) cells were rapidly and efficiently expanded ex vivo by >10.000-fold in the presence of appropriate cytokines[94]. On the other hand, constitutive expression of SALL4 was shown to possess oncogenic potential[95, 96] whereas Sall4 overexpression had a detrimental effect on hematopoiesis resulting in engraftment failure[97]. Consequently, care must be taken to achieve appropriately balanced Sall4 expression in ex vivo stem cell expansion applications and further studies are needed to ultimately determine its role in normal versus malignant hemopoiesis.…”