Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia

Abstract

Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on the redox-dependent signaling pathways involved in the leukemogenic process. Finally, the relevance of new chemotherapy options that specifically exert their pharmacological activity by altering the cellular redox imbalance will be discussed as an effective strategy to eradicate chemoresistant cells.

Exploring the Leukemogenic Potential of GATA-1S, the Shorter Isoform of GATA-1: Novel Insights into Mechanisms Hampering Respiratory Chain Complex II Activity and Limiting Oxidative Phosphorylation Efficiency

“…As a whole, these metabolic parameters suggest that, at least in part, the larger mitochondrial network in GATA-1 S cells is hindered to efficiently contribute to the oxidative metabolism due to molecular mechanisms limiting OXPHOS. In this regard, it is to be noted that these findings are in agreement with a large body of evidence indicating that, compared with their normal counterpart, AML cells display a larger mitochondrial network without increased respiratory chain activity alongside a lower spare reserve capacity that makes them more susceptible to oxidative stress [1][2][3]7,9,50]. In addition, the higher ECAR values detected in GATA-1 S cells correlates with an enhanced glycolytic flux that invokes the pseudo-hypoxic phenotype occurring when the HIF-1α pathway is constitutively activated, regardless of oxygen levels, a condition that, as above mentioned, characterizes cancer cells and can be driven by loss of complex II activity [24,68].…”

“…# p < 0.05, GATA-1 FL versus GATA-1 S * p < 0.05, ** p < 0.0001 versus mock control. Furthermore, our results in K562 cells showing enhanced glycolytic flux associated with GATA-1 S along with a large body of literature data reporting that increased glucose metabolism is a common feature of leukemia cells [55][56][57][58], linked to constitutively activation of HIF-1α pathway [3,59,60] prompted us to examine HIF-1α mRNA levels in these AML samples. Results showed significant increment of HIF-1α transcript levels at the diagnosis stage with respect to post-therapy and remission stages (Figure 9c).…”

“…In recent decades, there has been increasing recognition of the role played by mitochondria in maintaining hematopoietic stem cell (HSC) functions, with deregulated mitochondrial activities often preceding malignant transformation of myeloid precursors [1,2]. Along with changes in mitochondrial metabolism, oxidative stress resulting from abnormal reactive oxygen species (ROS) production is a common signature of myeloid leukemic cells and contributes to development and clonal expansion of leukemia stem cells (LSCs) by upregulating pathways that sustain cell proliferation, survival, invasion, migration, and metabolic adaptation [1,[3][4][5]. Furthermore, in comparison to normal cells, myeloid leukemia cells display an adaptive response to oxidative stress that is achieved by several mechanisms, including increasing antioxidant defenses representing a selective advantage that enhances cell survival under pro-oxidizing conditions [6][7][8][9][10][11].…”

The Multi-Omic Prognostic Model of Oxidative Stress-Related Genes in Acute Myeloid Leukemia

“…Acute myeloid leukemia, as a common malignancy, has seen an increasing mortality rate in recent years. Myeloid leukemia cells are inherently in a state of oxidative stress due to impaired ROS homeostasis, which is a common feature of several hematological malignancies ( Trombetti et al, 2021 ). ROS, as a product of normal cell metabolism, could regulate cell survival, proliferation, apoptosis, and cell cycle, as well as cell homeostasis.…”

Editorial: Metabolic Rewiring in Leukemias

“…The metabolic heterogeneity defines the tumor growth organization, promoting adaptability and resistance. One of the mechanisms by which metabolic connection is established in tumors is the oxidative stress (3). It induces autophagy with mitochondrial dysfunction and shift to high rates of glycolysis (4,5).…”