Abstract

LYL-1 is a basic Helix-Loop-Helix (bHLH) transcription factor closely related to TAL. Both LYL-1 and TAL were originally identified through their implication in T acute lymphocytic leukemia. Their bHLH domain seems functionally equivalent suggesting that these two proteins share some biological function. However LYL-1 and TAL diverge largely outside the bHLH region and display a distinct, yet overlapping, expression pattern in hematopoietic cells. The role of TAL on erythropoiesis remains controversial: it is required for proper erythroid and megakaryocytic differentiation, plays an important role in the proliferation of early erythroid progenitors (BFU-E) but appears dispensable for baseline and stress erythropoiesis. This minor erythroid defect in TAL-null mice suggests that another transcription factor may replace TAL during erythroid differentiation. Since LYL-1 is also expressed in erythroid cells, we assessed its role in erythropoiesis using knock-in mice. We show that mice deficient for LYL-1 have impaired erythropoiesis. Erythroid progenitor and erythroblast numbers were significantly increased in the spleen of LYL-1−/− mice while in bone marrow (BM) erythroblasts we observed a partial differentiation blockade and enhanced apoptosis associated with decreased Bcl-xL expression. More importantly, LYL-1−/− BM cells are severely impaired in their erythroid lineage competitive reconstituting abilities. Indeed, the reconstitution capacity of erythroid lineage with LYL-1−/− cells was drastically reduced of about 10-fold. Despite this reduced BM erythropoiesis, LYL-1−/− mice had stimulated erythropoiesis. Indeed, we found a significant rise in both BFU-E and CFU-E and erythroblasts cloning efficiencies in the spleen of LYL-1−/− mice. Thus, we wondered if a compensatory mechanism by TAL and GATA-1 was operating in LYL-1−/− mice. TAL and GATA-1 transcripts were more expressed in the mature erythroblast populations from the spleen of LYL-1−/− mice compared to control. As GATA-1 is necessary to activate stress erythropoiesis we investigated the role of LYL-1 in stress erythropoiesis by treating mice with phenylhydrazine (PHZ). LYL-1−/− mice were extremely sensitive to PHZ treatment with a rapid and profound drop in hematocrit followed by rapid recovery and associated with a significant rise in circulating reticulocytes and an increase of spleen CFU-E and BFU-E. Moreover, LYL-1−/− erythroid progenitors in BM and spleen displayed EPO hyper-responsiveness. In conclusion, our results definitely show modified erythropoiesis in LYL-1−/− mice that parallels the defects described in TAL−/− mice. Our results suggest that both transcription factors may have partially redundant functions on erythropoiesis, in contrast to their distinct function in HSCs that we previously described. Finally, double TAL−/− and LYL-1−/− KO mice may help to precisely understand the transcriptional regulation of erythropoiesis.

Disclosures: No relevant conflicts of interest to declare.

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