Smad4 stabilizes Hoxa9 proteins to the cytoplasm suggesting a protective role of Smad4 against nuclear activation by Hoxa9 and leukemia transformation. (A) Illustration of the model of leukemogenesis involving regulation of two pathways; the TGF-β and the Hoxa9 pathways as respectively negative and positive regulators of primitive hematopoietic cell expansion in normal conditions (normal). Under forced expression of HOXA9 in Wt cells, Smad4 stabilizes Hoxa9 to the cytoplasm and therefore protects primitive hematopoietic cells against increased nuclear activation by Hoxa9. In Smad4^−/− primitive hematopoietic cells, this protective mechanism cannot be operated which leads to increased concentration of Hoxa9 in the nucleus; increased transcriptional activation by Hoxa9 in primitive hematopoietic cells is increased making them vulnerable to leukemia transformation (leukemia mechanism). (B) Reactivation of the Smad pathway ensues on expression of a 20aa peptide mimicking a small portion of the MH1 domain by releasing the Smad4 to activate its targets and to induce apoptosis (leukemia treatment).