Targeting Leukemia Stem Cell-Niche Dynamics: A New Challenge in AML Treatment

Abstract

One of the most urgent needs in AML is to improve the disease cure rate as relapse still occurs in 60–80% of patients. Recent evidence suggests that dismal clinical outcomes may be improved by a better definition of the tight interaction between the AML cell population and the bone marrow (BM) microenvironment (“the niche”); the latter has been progressively highlighted to have an active role in the disease process. It has now been well established that the leukemic population may misinterpret niche-derived signals and remodel the niche, providing a shelter to AML cells and protecting them from the cytotoxic effects of chemoradiotherapy. Novel imaging technological advances and preclinical disease models have revealed that, due to the finite number of BM niches, leukemic stem cells (LSCs) and normal hematopoietic stem cells (HSCs) compete for the same functional areas. Thus, the removal of LSCs from the BM niche and the promotion of normal HSC engraftment should be the primary goals in antileukemic research. In addition, it is now becoming increasingly clear that AML-niche dynamics are disease stage specific. In AML, the niche has been linked to disease pathogenesis in the preleukemic stage, the niche becomes permissive once leukemic cells are established, and the niche is transformed into a self-reinforcing structure at a later disease stage. These concepts have been fostered by the demonstration that, in unrelated AML types, endosteal vessel loss occurs as a primary AML-induced niche alteration, and additional AML-induced alterations of the niche and normal hematopoiesis evolve focally and in parallel. Obviously, this endosteal vessel loss plays a fundamental role in AML pathogenesis by causing excessive vascular permeability, hypoxia, altered perfusion, and reduced drug delivery. Each of these alterations may be effectively targeted by various therapeutic procedures, but preservation of endosteal vessel integrity might be the best option for any future antileukemic treatment.

Hypoxia–CXCL6 axis affects arteriolar niche remodeling in acute myeloid leukemia

“…As a result, it is suggested that the best treatment strategy is to prevent AML-induced hypoxia leading to arteriole loss in the endosteum, so as to prevent the development of AML due to the hypoxia area (the real “shelter” of LSCs) derived from BM niche. 26 Some studies have made efforts to this end. For example, it was found that the ECs of AML mice model produced more nitric oxide, and the recovery of normal vascular function in BM through nitric oxide synthetase (NOS) inhibition improved the treatment response.…”

Hematopoietic Cell Kinase (HCK) Is a Player of the Crosstalk Between Hematopoietic Cells and Bone Marrow Niche Through CXCL12/CXCR4 Axis

“…The crosstalk between leukemic stem/progenitor cells and bone marrow microenvironment has been highlighted as an important process for the resistance to chemotherapy and disease relapse in AML, mainly through the activation of the CXCL12/CXCR4 pathway ( Bernasconi and Borsani, 2019 ).…”

Driving CAR T Stem Cell Targeting in Acute Myeloid Leukemia: The Roads to Success

“…The appearance of these changes observed in the BM niche follows a specific temporal order, reflecting the AML developmental phase. The establishment of a pre-leukemic niche is followed by the development of a leukemia-permissive and lately self-reinforcing environment [ 52 ]. Some of these alterations, such as the microvessel density, the loss of nestin expression (indicator of nerve damage), and the aberrant cellular composition of the BM mesenchymal and osteoblastic compartments, have been correlated to AML clinical features, such as aggressiveness, sensitivity to treatment, and patients’ overall survival [ 47 , 48 , 49 ].…”