| SALL4 is a zinc‑finger transcription factor of the mammalian spalt family that occupies a central position in stem cell transcriptional networks, where it maintains pluripotency and self‑renewal in embryonic stem cells and supports the expansion and fate control of hematopoietic stem and progenitor cells by orchestrating both genetic and epigenetic programs. The protein contains multiple C2H2 zinc‑finger clusters that confer sequence‑specific DNA binding, together with low‑complexity regions that mediate interactions with cofactors such as Nanog, Oct4, Sox2, DNA methyltransferases and epigenetic complexes, allowing SALL4 to act in different stem cell lineages through distinct transcriptional circuitries despite a shared core structural framework. In embryonic stem cells, SALL4 binds a highly conserved distal enhancer of Pou5f1 and activates Oct4 transcription, and reduction of SALL4 levels causes respecification of ES cells toward trophoblast fates with expansion of Cdx2 expression, demonstrating that SALL4 functions as a direct transcriptional activator of Oct4 and is required for maintaining the ESC pluripotent state and early embryonic cell‑fate decisions. Genome‑wide mapping reveals that SALL4 co‑occupies many Nanog and Oct4 sites and regulates large sets of pluripotency genes, while lineage analyses show that SALL4 modulates distinct transcription circuits in embryonic stem cells versus extraembryonic endoderm stem cells, emphasizing its role as a versatile regulator that adapts its target repertoire to specific blastocyst‑derived lineages. In normal hematopoiesis, SALL4 is selectively expressed in primitive CD34+ hematopoietic stem and progenitor cells, is rapidly downregulated as these cells differentiate, and is absent in mature myeloid populations, and forced expression of SALL4A or SALL4B in mouse Lin−/Sca1+/c‑Kit+ LSK cells drives sustained ex vivo proliferation, expansion of functional HSC/HPC pools and enhanced long‑term multilineage repopulation after transplantation, whereas downregulation of endogenous SALL4 reduces LSK proliferation and accelerates differentiation. These stem‑cell‑enhancing activities are accompanied by strong upregulation of key HSC/HPC regulators including HoxB4, Notch1, Bmi‑1, Runx1, Meis1 and NF‑YA, placing SALL4 at the top of a transcriptional hierarchy that boosts self‑renewal and inhibits granulocytic differentiation in myeloid progenitors, and providing a basis for using SALL4 manipulation as a strategy for large‑scale expansion of clinically transplantable stem cells. At the mechanistic level, SALL4 engages epigenetic machinery by binding DNA methyltransferases and associating with their enzymatic activities, increasing global DNA methylation when overexpressed and repressing transcription of targets such as PTEN through recruitment of the NuRD complex, while also activating Bmi‑1 and interacting with Wnt/β‑catenin signaling, generating a SALL4/Wnt/Bmi‑1/PTEN network that integrates chromatin modification with stemness and leukemic transformation. Dysregulated SALL4 expression is reactivated in acute myeloid leukemia and multiple solid tumors, where constitutive SALL4 expression in transgenic mice induces AML and cancer studies show that SALL4 drives proliferation, survival, chemoresistance and maintenance of cancer stem cells through genetic and epigenetic control of downstream oncogenic pathways, making SALL4 a robust cancer biomarker and emerging therapeutic target. |
