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D. Forte et al.
through a metabolic shift from OXPHOS to fatty acid oxi- dation, which causes OXPHOS uncoupling.16 In addition, leukemia stem cells express the fatty acid receptor CD36 and exhibit high levels of fatty acid oxidation, associated with cell quiescence and drug resistance.17 However, a novel small molecule inhibitor of fatty acid oxidation, avocatin-B, selectively inhibits AML and leukemia stem cells without detectable toxicity in normal HSC. Avocatin-B increases fatty acid uptake and enhances the expression of fatty acid- binding protein-4 (FABP4) in adipocytes co-cultured with AML cells. However, concomitantly, avocatin-B increases glucose uptake and glycolysis in AML, thus contributing to AML survival.18 Overall, these data highlight the limitations of targeting a single metabolic pathway, since leukemic cells may escape through metabolic adaptation. Accordingly, cytarabine-resistant AML cells exhibit increased fatty acid oxidation and OXPHOS. Fatty acid oxidation inhibition induces an energy shift from high to low OXPHOS that enhances anti-leukemia effects, but only in combination with cytarabine.19 Inhibition of fatty acid oxidation addi- tionally activates the endoplasmic reticulum stress activator transcription factor 4 (ATF4) and enhances cytarabine cytoxicity in AML cells co-cultured with bone marrow adipocytes.20 These findings suggest that combined thera- pies containing inhibitors of fatty acid oxidation could be capable of targeting metabolic vulnerabilities in AML.
Inflammation and cell cycle
One hallmark of hematologic malignancies is a proin- flammatory state whereby inflammatory cytokines affect the proliferation of normal and mutant cells. Inflammation is, therefore, one key trigger of the reshaped malignant microenvironment.
Impact of aged marrow macrophages on hematopoietic stem cells and their niche
Microenvironmental inflammation is another driver of hematopoietic aging. Previous studies have shown that aged CD41+ LT-HSC accumulate during aging and their megakaryocyte bias results in increased circulating platelets in aged mice.21-24 Calvi et al. have shown that aged bone marrow macrophages contribute to the expansion of platelet-based HSC through interleukin-1β.25 Aged murine bone marrow macrophages exhibit an activated phenotype and defective phagocytic function, which causes reduced efferocytosis of senescent neutrophils. In vitro co-culture systems suggest that increased interleukin-1β and reduced Axl receptor tyrosine kinase and its associated protein growth arrest-specific 6 (Gas6) contribute to platelet skew- ing during aging.
Hematopoietic stem cells and their bone marrow niche under inflammatory stress
Inflammation can affect both HSC and their niches. Infection can cause stress and dysfunction in HSC respond- ing to infection. Chemotherapy, transplantation or inflam- matory cytokines, such as interferon (IFN)-α, can modify HSC quiescence and make HSC re-enter the cell cycle.26-29 For example, acute or non-acute virus infections activate quiescent LT-HSC but also affect their function through IFN- I receptor signaling.29 Non-acute murine cytomegalovirus infections alter the LT-HSC gene expression profile and impair HSC function upon transplantation. One mediator
appears to be the extracellular matrix adaptor protein Matrilin-4 (Matn4), which is a candidate negative regulator of HSC proliferation under stress.29 Under acute stress, Matn4 expression decreases, allowing for HSC expansion to replenish the blood system. Importantly, reduced expression of the Cxcl12/Sdf-1 receptor Cxcr4 in Matn4-/- HSC improves the reconstitution and expansion of HSC. On the non-hematopoietic side, endothelial cells proliferate after inflammatory stress or infection to maintain vessel integrity and permeability. The responses of endothelial cells to IFN- α in vivo are transient and dependent on the expression of IFN-α receptors. In this regard, vascular endothelial growth factor (VEGF) has emerged as one mediator of the activation of bone marrow endothelial cells by IFN-α-stimulated hematopoietic cells. In conclusion, as part of the dynamic crosstalk between HSC and their niches, inflammatory stress not only has an impact on HSC but also on their microenvironment and this altered bidirectional crosstalk affects the growth and function in each compartment.
The bone marrow microenvironment in myeloproliferative neoplasms
Associated with inflammation, bone marrow fibrosis is an extensive remodeling of the bone marrow extracellular matrix, which is typically observed in some myeloprolifer- ative neoplasms. Previous studies found that damage to the bone marrow microenvironment contributes to the pro- gression of myeloproliferative neoplasms.30 However, the identification of fibrosis-driving cells and specific markers of a pre-fibrotic state are important therapeutic issues that remain only partially addressed. Schneider and colleagues described GLI family zinc finger 1 (Gli1)+ mesenchymal stromal cells as fibrotic cells in different types of fibrosis. Gli1+ cells appear to be myofibroblast precursors which contribute significantly to myelofibrosis. Accordingly, genetic ablation of Gli1+ cells reduces fibrosis and improves hematopoiesis in experimental models.31
Regulation of dormant hematopoietic stem cells
Inflammation is only one of the mechanisms that can awaken dormant HSC, as shown in studies by Cabezas- Wallscheid and colleagues. Dormant HSC can now be iden- tified with specific markers, such as Lineage−Sca-1+c-Kit+ (LSK) CD150+CD48−CD135−CD34− cells expressing the G protein-coupled receptor Gprc5c5.32 Dormant HSC repre- sent only a very small subset of bone marrow cells, but these cells harbor the highest long-term reconstituting potential. Dormant HSC are characterized by low levels of biosynthetic processes (transcription, mRNA processing and translation) which gradually increase as the HSC become activated. Retinoic acid/vitamin A-induced signal- ing is highly enriched in dormant HSC and contributes to maintain low levels of reactive oxygen species, protein translation and expression of the proto-oncogene c-myc in these cells. In vivo, pre-treatment with all-trans retinoic acid can preserve HSC quiescence upon stress induced by chemotherapy or lipopolysaccharide. These results suggest that retinoic acid might restrict HSC proliferation. In con- trast, lack of vitamin A compromises HSC re-entry into dor- mancy after exposure to inflammatory stress.32
Molecular regulation and heterogeneity in the exit from quiescence by human hematopoietic stem cells
Not only the actual quiescence of HSC, but also the time that that these cells take to enter the cell cycle can be a
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haematologica | 2019; 104(10)