Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

Abstract

Acute myeloid leukemias (AML) comprise a wide array of different entities, which have in common a rapid expansion of myeloid blast cells leading to displacement of normal hematopoietic cells and also disruption of the microenvironment in the bone marrow niches. Based on an insight into the complex cellular interactions in the bone marrow niches in non-neoplastic conditions in general, this review delineates the complex relationship between leukemic cells and reactive cells of the tumor microenvironment (TME) in AML. A special focus is directed on niche cells and various T-cell subsets as these also provide a potential therapeutic rationale considering e.g. immunomodulation. The TME of AML on the one hand plays a vital role for sustaining and promoting leukemogenesis but - on the other hand - it also has adverse effects on abnormal blasts developing into overt leukemia hindering their proliferation and potentially removing such cells. Thus, leukemic cells need to and develop strategies in order to manipulate the TME. Interference with those strategies might be of particular therapeutic potential since mechanisms of resistance related to tumor cell plasticity do not apply to it.

Roads of Drug Resistance in Acute Myeloid Leukemia – Is It a Dead End?

“…Hematopoietic stem cells are maintained by stem cell factor (SCF), CXCL12 (C-X-C Motif Chemokine Receptor 4), Notch ligands, and transforming growth factor-β [59]. Mesenchymal stromal cells secrete SCF and CXCL12, which regulate leukocyte migration [60]. The binding of CXCL12 to its receptor CXCR4 initiates the phosphorylation of CXCR4 and activates prosurvival signaling pathways such as MEK/ERK, JAK/STAT, and PI3K/ AKT cascades [58].…”

The Role of Immune Checkpoint Blockade in Acute Myeloid Leukemia

“…Nowadays, the immune system has a significant role in tumor cell elimination. In AML, a common problem is tumor cell immune escape, being an effective survival mechanism [35,36]. AML blast cells have the capacity to block immune system communication and weaken T-cells, namely in their cytotoxic activity.…”

“…On the other hand, T-cell anergy can also be induced through T-cell immunoglobulin and mucin domain 3 (TIM3), which binds to and is activated by galectin-9, which is highly expressed in AML blasts [43]. Another suppressive molecule is an inducible T-cell co-stimulator ligand (ICOSL) and IDO's that contribute to Tregs expansion and an immunosuppressive environment and at the same time restrict cytotoxic activity [36,44,45]. High expression levels of PD1/PD-L1 and TIM3 are correlated with a worse prognosis in AML [36,46].…”

“…Another suppressive molecule is an inducible T-cell co-stimulator ligand (ICOSL) and IDO's that contribute to Tregs expansion and an immunosuppressive environment and at the same time restrict cytotoxic activity [36,44,45]. High expression levels of PD1/PD-L1 and TIM3 are correlated with a worse prognosis in AML [36,46].…”

Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine

“…Studies have proved that AML has varieties of drug resistance mechanisms, including adaptive cytoprotection mechanism ( 1 ), tumor microenvironment protection ( 2 , 3 ), autophagy ( 4 ), and epigenetic mutation ( 5 ). In addition, chemotherapy often accompany with DNA damage.…”