Gadd45 Genes Participate In Myeloid Cell Fate Determination

The gadd45 family of genes is rapidly induced by different stressors, including differentiation-inducing cytokines, and there is a large body of evidence that their cognate proteins are key players in cellular stress responses. Gadd45 gene(s) were found to be primary response gene(s) to IL-6 mediated terminal differentiation of M1 monocytic leukemia cells, as well as to G-CSF mediated terminal differentiation of 32Dcl3 cells; furthermore, gadd45 gene(s) were induced by myeloid differentiation inducing cytokines such as IL-3 and GM-CSF in primary murine bone marrow (BM) cells (Zhang et al., Oncogene 18:4899–4907, 1999; Abdollahi et al, Oncogene 6:165–167, 1990). Induction of gadd45 genes at the onset of myeloid differentiation suggested that Gadd45 protein(s) play a role in hematopoiesis, yet no apparent abnormalities were observed in either the BM or peripheral blood compartments of mice deficient for either gadd45a or gadd45b. Both BM and Hoxb8 immortalized macrophage progenitors induced to differentiate in vitro revealed that deficiency in either gadd45a or gadd45b resulted in loss of macrophages and an increase in neutrophils compared to cells derived from wild type mice. How Gadd45a and Gadd45b influence the expression and activation of transcription factors that regulate myeloid cell determination will be discussed.