Autophagy in the Hematopoietic System

Autophagy, the major lysosomal degradation pathway in the cell plays a key role in the maintenance of metabolism, healthy mitochondria and limits reactive oxygen species, thus keeping the genome and proteome healthy. We demonstrated that erythroblasts rely on mitophagy as they differentiate into erythrocytes ¹ and that hematopoietic stem cells (HSCs) require autophagy to survive and repopulate a new hematopoietic system ². Genetic ablation of Atg7 in the hematopoietic system, which encodes a component of the autophagy system, resulted in a pre-leukemic phenotype, which predicted low autophagic flux found in blasts from patients with acute myeloid leukemia ³. Most recently, our studies indicate that autophagy provides free fatty acids for neutrophil differentiation by degrading lipid droplets ⁴. However, it is not clear what is degraded by autophagy in HSCs or whether autophagy is required to provide building blocks to the HSC and what the nature of these building blocks is. We are currently addressing this by using state-of-the-art in vivo techniques, and I will report our findings in my presentation.

1 Mortensen, M., Ferguson, D. J., Edelmann, M., Kessler, B., Morten, K. J., Komatsu, M. & Simon, A. K. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci U S A 107, 832-837, doi:10.1073/pnas.0913170107 (2010).

2 Mortensen, M., Soilleux, E. J., Djordjevic, G., Tripp, R., Lutteropp, M., Sadighi-Akha, E., Stranks, A. J., Glanville, J., Knight, S., Jacobsen, S. E., Kranc, K. R. & Simon, A. K. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 208, 455-467, doi:10.1084/jem.20101145 (2011).

3 Watson, A. S., Riffelmacher, T., Stranks, A., Williams, O., De Boer, J., Cain, K., MacFarlane, M., McGouran, J., Kessler, B., Khandwala, S., Chowdhury, O., Puleston, D., Phadwal, K., Mortensen, M., Ferguson, D., Soilleux, E., Woll, P., Jacobsen, S. E. & Simon, A. K. Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia. Cell Death Discov 1, doi:10.1038/cddiscovery.2015.8 (2015).

4 Riffelmacher, T., Clarke, A., Richter, F. C., Stranks, A., Pandey, S., Danielli, S., Hublitz, P., Yu, Z. R., Johnson, E., Schwerd, T., McCullagh, J., Uhlig, H., Jacobsen, S. E. W. & Simon, A. K. Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity 47, 466-480, doi:10.1016/j.immuni.2017.08.005 (2017).