CDX4 is a homeodomain transcription factor that functions as a critical regulator of hematopoietic development and HOX gene expression. As a DNA-binding transcription activator, CDX4 regulates transcription of HOXA9 and HOXA10 genes and participates in anterior/posterior axis specification during embryonic development 1. CDX4 is normally expressed in early hematopoietic progenitors but is aberrantly expressed in approximately 25% of acute myeloid leukemia (AML) patient samples 2. CDX4 operates within positive feedback loops: HoxA10 activates CDX4 transcription while Cdx4 reciprocally activates HOXA10 expression, with β-catenin further amplifying this regulatory circuit 34. During normal myelopoiesis, HoxA9-mediated phosphorylation silences CDX4 expression, but this mechanism is disrupted in leukemias with MLL1 translocations or Shp2 activation 1. Dysregulated CDX4 expression drives acute erythroid leukemia (AEL) by inducing stemness genes while suppressing GATA1/GATA2-dependent erythroid differentiation programs 5. CDX4 cooperates with Meis1a to induce fully penetrant AML in murine models, requiring intact transactivation and DNA-binding domains 2. CDX4+CD1d+ mesoderm marks progenitors with definitive hematopoietic potential during human development 6. These findings establish CDX4 as a master regulator whose dysregulation contributes centrally to acute leukemogenesis.