SKIDA1 Selectively Sustains MLL-ENL-Expressing Hematopoietic Stem and Progenitor Cells

Chromosomal translocations involving the MLL1 gene often drive infant acute myeloid leukemia (AML). MLL fusion proteins (e.g., MLL-ENL, MLL-AF9, MLL-AF10) activate self-renewal programs in hematopoietic stem and progenitor cells, ultimately leading to transformation. The high frequency of MLL1 rearrangements in infant leukemias suggests that neonatal progenitors are uniquely poised to transform in response to these mutations. Indeed, we have recently shown that MLL-ENL initiates AML more efficiently in neonatal progenitors than in adult progenitors (Okeyo-Owuor et. al. Blood Advances, 2019). This raises the question of whether MLL-ENL induces key effectors of transformation more efficiently in neonatal progenitors than in adult progenitors. We identified Ski/Dach Domain Containing 1 (Skida1) as a gene that is highly induced by MLL-ENL in neonatal, but not adult hematopoietic progenitors. SKIDA1 is also highly expressed in human pediatric AML, and this expression is largely restricted to leukemias with MLL1 rearrangements. These observations suggest that Skida1 may be a critical, neonate-specific effector of MLL-ENL driven leukemogenesis.