Leukemia Stem Cell Release From the Stem Cell Niche to Treat Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous, complex, and deadly disease, whose treatment has hardly evolved for decades and grounds on the use of intensive chemotherapy regimens. Chemotherapy helps reduce AML bulk, but promotes relapse in the long-run by selection of chemoresistant leukemia stem cells (LSC). These may diversify and result in progression to more aggressive forms of AML. In vivo models suggest that the bone marrow stem cell niche helps LSC stay dormant and protected from chemotherapy. Here, we summarize relevant changes in stem cell niche homing and adhesion of AML LSC vs. healthy hematopoietic stem cells, and provide an overview of clinical trials aiming at targeting these processes for AML treatment and future directions within this field. Promising results with various non-mutation-targeted novel therapies directed to LSC eradication via interference with their anchoring to the stem cell niche have encouraged ongoing or future advanced phase III clinical trials. In the coming years, we may see a shift in the focus of AML treatment to LSC-directed therapies if the prospect of improved cure rates holds true. In the future, AML treatment should lean toward personalized therapies using combinations of these compounds plus mutation-targeted agents and/or targeted delivery of chemotherapy, aiming at LSC eradication with reduced side effects.

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

“…However, the phase II trial of AS101 has been suspended (NCT01010373). Several other compounds targeting LSC release from the bone marrow niche have been tested and recently reviewed [ 120 ]. Although we acknowledge the limitations of extrapolating those results to patients with leukostasis, the central role of selectins in the adherence of leukemic blasts to endothelial cells and the contribution to leukostasis might make such an approach a potentially promising target.…”

Cadherins, Selectins, and Integrins in CAM-DR in Leukemia

“…Secondly, in an AML mouse model, LSCs adhered to the vascular niche which protected LSCs from chemotherapy through E-selectin/Eselectin ligands and this effect was ameliorated by GMI-1271 (28). Thirdly, VLA-4 is one of the most prominent integrins involved in LSCs (24). Recently a study showed that inhibition of Kindlin-3-mediated VLA-4 adhesion mobilized LSCs in the BM and prolonged survival of mice with CML (29).…”

“…LSCs are capable of self-renewal and thus able to maintain survival in optimized in vitro co-culture systems and in immunocompromised mice, which have been defined in AML and CML (22). CAMs play an important role in the interaction between LSCs and the hematopoietic niche (23,24). Firstly, it has been shown that N-cadherin positive CD34 + CD38 − LSCs population has a critical role in the development of AML (25,26).…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…HSC rolling and homing is mediated by interaction between constitutively expressed E- and P- selectins and VLA4, where SDF1 and its receptor CXCR4 acts as a chemo-attractant through β1/2− integrins and SDF1 for stable engraftment [ 23 , 25 , 152 , 153 , 154 , 155 , 156 ]. BCR-ABL1 impairs the SDF1/CXCR4 axis in normal HSCs but upregulates it in CML stem cells, conferring selective homing and survival in the BM niche [ 17 , 23 , 152 , 153 , 157 , 158 ]. In addition, CML stem cells have defective β1-integrin levels (VLA4 or VLA5), allowing redistribution and mobilization into the PB and other organs, e.g., spleen with the potential of uncontrolled extramedullary myeloproliferation and local LSC reservoirs [ 152 , 154 , 157 ].…”

“…BCR-ABL1 impairs the SDF1/CXCR4 axis in normal HSCs but upregulates it in CML stem cells, conferring selective homing and survival in the BM niche [ 17 , 23 , 152 , 153 , 157 , 158 ]. In addition, CML stem cells have defective β1-integrin levels (VLA4 or VLA5), allowing redistribution and mobilization into the PB and other organs, e.g., spleen with the potential of uncontrolled extramedullary myeloproliferation and local LSC reservoirs [ 152 , 154 , 157 ]. CML stem cells alter extrinsic factors and upregulate expression of CD44 + and E-selectin to promote prominent BMM changes such as marrow fibrosis for exclusive stem cell engraftment and dormancy, offering protection from drug-targeting [ 25 , 152 , 154 , 158 , 159 , 160 , 161 , 162 ].…”