Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1

Abstract

Key Points• TPO specifically activates Erk and NF-kB pathways in hematopoietic stem and progenitor cells.• Erk and NF-kB cooperate to trigger their common target, Iex-1, and DNA-PKdependent NHEJ activation in HSPCs upon irradiation.Loss of hematopoietic stem cell (HSC) function and increased risk of developing hematopoietic malignancies are severe and concerning complications of anticancer radiotherapy and chemotherapy. We have previously shown that thrombopoietin (TPO), a critical HSC regulator, ensures HSC chromosomal integrity and function in response to g-irradiation by regulating their DNA-damage response. TPO directly affects the double-strand break (DSB) repair machinery through increased DNA-protein kinase (DNA-PK) phosphorylation and nonhomologous end-joining (NHEJ) repair efficiency and fidelity. This effect is not shared by other HSC growth factors, suggesting that TPO triggers a specific signal in HSCs facilitating DNA-PK activation upon DNA damage. The discovery of these unique signaling pathways will provide a means of enhancing TPO-desirable effects on HSCs and improving the safety of anticancer DNA agents. We show here that TPO specifically triggers Erk and nuclear factor kB (NF-kB) pathways in mouse hematopoietic stem and progenitor cells (HSPCs). Both of these pathways are required for a TPO-mediated increase in DSB repair. They cooperate to induce and activate the early stress-response gene, Iex-1 (ier3), upon DNA damage. Iex-1 forms a complex with pERK and the catalytic subunit of DNA-PK, which is necessary and sufficient to promote TPO-increased DNA-PK activation and NHEJ DSB repair in both mouse and human HSPCs. (Blood. 2014;123(4):509-519)

Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

“…In support, disruption of ROS homeostasis has been shown to impede the quiescence of hematopoietic stem cells, a paradigm corroborated by our current investigations [21, 37, 38]. Alongside the current research, another recent publication showed that IEX-1 was a key to up regulate NF-kB and to activate Erk signaling resulting in repairing DNA breaks induced by gamma-irradiation in hematopoietic stem cells [39]. The two studies, one employing TPO receptor and the other using IEX-1 knockout mice by us, converge in support of a role for IEX-1 in maintaining homeostasis of hematopoietic stem cells under stress.…”

The autotaxin–LPA 2 GPCR axis is modulated by γ-irradiation and facilitates DNA damage repair

“…We hypothesize that DNA-PK could be the convergence point downstream signals from ERK. A recent study demonstrated that in mouse hematopoietic stem and progenitor cells exposed to irradiation and trombopoietin treatment activated ERK and NF-κB pathways, which in turn induced the upregulation of their common target, the early stress response gene Iex-1, leading to enhancement of DNA-PK activity and nonhomologous end joining (NHEJ) [40]. Kriegs et el [41] reported the role of MAPK signaling in EGFR-mediated DSB repair based on evidence that inhibition of ERK blocked the NHEJ.…”

The Role of Iex-1 in the Pathogenesis of Venous Neointimal Hyperplasia Associated with Hemodialysis Arteriovenous Fistula

“…In cardiomyocytes, Iex-1 has been shown to be anti-hypertrophic and lead to apoptosis [21]. In other studies, overexpression of Iex-1 has been shown to cause proliferation mediated via a NF-κβ pathway in response to shear stress [22]. Finally, it has also been shown to lead to cellular proliferation in vascular smooth muscle cells [21], [23].…”