Loss of and Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size.

A germ line copy number duplication of chromosome 14q32, which contains and , was identified in families with myeloproliferative neoplasm (MPN). Here, we show that mice lacking both and , but not either alone, exhibited decreased hematopoiesis, resulting in death accompanied by anemia. In marked contrast to MPN patients with duplication of and , the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double-knockout fetal livers was significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of or alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that and play a synergistic effect in maintaining the pool size of HSCs.