Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia

Abstract

Aging is associated with various hematological disorders and a higher risk of myeloproliferative disorders. An aged hematopoietic system can be characterized by decreased immune function and increased myeloid cell production. Hematopoietic stem cells (HSCs) regulate the production of blood cells throughout life. The self-renewal and regenerative potential of HSCs determine the quality and quantity of the peripheral blood cells. External signals from the microenvironment under different conditions determine the fate of the HSCs to proliferate, self-renew, differentiate, or remain quiescent. HSCs respond impromptu to a vast array of extracellular signaling cascades such as cytokines, growth factors, or nutrients, which are crucial in the regulation of HSCs. Early growth response factor 1 (EGR1) is one of the key transcription factors controlling HSC proliferation and their localization in the bone marrow (BM) niche. Downregulation of Egr1 activates and recruits HSCs for their proliferation and differentiation to produce mature blood cells. Increased expression of Egr1 is implicated in immuno-aging of HSCs. However, dysregulation of Egr1 is associated with hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). Here, we summarize the current understanding of the role of EGR1 in the regulation of HSC functionality and the manifestation of leukemia. We also discuss the alternative strategies to rejuvenate the aged HSCs by targeting EGR1 in different settings.

Keywords: HSC activation; HSC rejuvenation; aged HSCs; early growth response 1 (EGR1); hematopoitic stem cells; leukemia.

FIGURE 1

EGR1 targeting strategies for rejuvenation of aged Hematopoietic Stem Cells. The expression of the zinc finger transcription factor - EGR1 is significantly increased in aged HSCs. This is, at least partially, mediated by the aging-associated changes in the BM niche. Increased EGR1 activation in the aged HSCs hampers their self-renewal activity and functions. EGR1 targeting strategies may be used to explore the possibility to rejuvenate aged HSCs. These strategies include - (A) Using the vesicle-mediated transfer of anti-Egr1 oligos specifically targeting aged HSCs. (B) Developing pharmacological EGR1 inhibitors. (C) Treating aged HSCs with recombinant Netrin-1 protein to reduce EGR1 activation in them. (D) Ectopic expression of Netrin-1 in aged BM niche cells to rescue Netrin-1 -Neogenin-1 interaction to modulate downstream EGR1 levels in the aged HSCs.