A Gene-Targeted Mouse Model for Bone Marrow Failure Syndrome.

Bone marrow failure is a disease syndrome characterized by dysfunction of bone marrow to produce mature blood cells. However, molecular mechanisms causing the disease syndromes remain remarkably obscure. We generated mice homozygous for an inactivating mutation of the Translin gene. Most of the aged mutant mice (Translin^−/−) were found to exhibit progressive bone marrow dysfunction manifested by a reduction in immature myeloid cells and erythroblasts, and eventually developed marked splenomegaly, with up to 30-fold elevation in weight. Histological examination of enlarged spleens revealed extramedullary hematopoiesis, prominent expansion of the red pulp areas with an increase in the number of mature granulocytes and a marked lack of immature myeloid cells. Furthermore, these mice also featured complete loss of immature myeloid cells and erythroblasts in bone marrow. On the other hand, an increase in the number of reticulocytes (over 10 %) and unusual appearance of metamyelocytes and orthochromatic erythroblasts were seen in peripheral blood. A cascade of the lineage-restricted transcription factors is known to determine developmental decisions regarding hematopoiesis. How levels of transcription factors are translated into a decision to control lineage commitment is an intriguing question in hematopoiesis which remains to be explored. Therefore, we considered the bone marrow failure in aged Translin^−/− might be due to decreased expression of the Ets family transcription factor PU.1 that has previously been suggested to be essential for myeloid development. However, quantitative RT-PCR analysis showed PU.1 mRNA to be expressed at equivalent levels in bone marrows of mutant and wild mice. In contrast, our data indicated a sharp reduction of the mRNA levels of the basic helix-loop-helix (bHLH) protein, E2A and its dimerization partner, TAL1, suggesting a contribution of E47/TAL heterodimer having distinctive DNA-binding properties for fine tune control of gene expression during hematopoiesis. In conclusion, the present studies demonstrated that expression levels of Translin are crucial to the bone marrow’s functional ability, and that our findings will shed light on the molecular events involved in bone marrow failure syndromes.