Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche

Abstract

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell–cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.

Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

“…AML cells are known to exhibit high levels of ROS 52,53 . However, our data has shown that AML cells in co-culture present lower levels of ROS than AML cells cultured alone, which is in agreement with recent studies in primary AML and mesenchymal stromal cell co-cultures 14,24 . The current mechanisms to describe this phenomenon involve mitochondrial transfer and activation of glutathione-related antioxidant pathways 14,24 , although previous data on haematopoietic stem cells (HSCs) revealed that HSCs can directly transfer ROS via gap junctions to stromal cells 32 .…”

“…For instance, it was reported that Nestin+ bone marrow mesenchymal stem cells (BMSCs) support AML progression by increasing the bioenergetic capacity of AML cells and providing them with glutathione (GSH)-mediated antioxidant defence to balance the excess ROS [14]. Similarly, a recent study showed that co-culturing BMSCs with AML cells leads to a decrease in AML ROS levels due to an activation of the antioxidant enzyme GPx-3 in AML cells [24].…”

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…In leukemic cells, the presence of BM-MSCs promotes the overexpression of GPX3, the cytoplasmic relocalization of Nrf2, and inactivation of p38MAPK with a concomitantly decrease in ROS levels. Of note, a reverse effect was observed in BM-MSCs in contact with leukemic cells, with a particular rise in ROS levels, decrease in GPX3 expression, and nuclear relocalization of Nrf2 [ 118 ]. One explanation could be ascribable to a mechanism of ROS transfer between AML cells and MSCs mediated by Connexin(CX)-43, a gap junction protein [ 119 ].…”

Circular RNA ATAD1 is upregulated in acute myeloid leukemia and promotes cancer cell proliferation by downregulating miR‑34b via promoter methylation

“…Leukemia initiating cells (LICs) interact with their surrounding bone marrow microenvironment ( 22 ), and the complex cell network surrounding LICs determines their fate ( 23 ). Various cellular signaling pathways and metabolic mechanisms regulate the BMMNC microenvironment and contribute to AML development ( 24 , 25 ). However, the detailed regulation mechanism for BMMNC malignant transformation has not been clearly defined.…”