Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis

Abstract

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.

Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA

“…2 We confirmed BM engraftment in recipients by flow cytometry, and using both histological and radiological techniques, we could demonstrate that they had patterns of CNS involvement mimicking those seen in patients with CNS disease (supplemental Figures 1 and 2). B-ALL cells have an inherent capacity to infiltrate the CNS, 3 and we observed that by 6 months, recipient mice had CNS disease, regardless of whether the patients whose leukemic cells they received had CNS disease at the time the cells were donated for research.…”

Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

“…27; Central Institute of Experimental Animals, Kawasaki, Japan) were transplanted with SU-Ph2 or SU/SR cells (1 Â 10 6 cells) through the tail vein without preconditioning. Three weeks after transplantation, when engraftment of leukemia cells was confirmed in bone marrow, imatinib (400 mg/kg/dose) or PD0332991 (150 mg/kg/dose) dissolved in deionized water or deionized water as the vehicle was orally administered through a gastric tube.…”

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

“…26 In brief, PB mononuclear cells (PBMCs) obtained from TAM patients (1-3 3 10 6 cells) were injected into 2.4 Gy-irradiated 8-to 12-week-old NOG mice through the tail vein. To screen for the proliferation of TAM-derived cells, bone marrow (BM) cells were aspirated from the tibia every 4 weeks.…”

“…We previously described the development of novel immunodeficient NOD/Shi-scid, interleukin (IL)-2Rg null (NOG) mice with a superior capacity for the engraftment of human hematopoietic and neoplastic cells. [23][24][25][26] In contrast to a previous study in which TAM cells showed a limited ability to expand in immunodeficient mice, 27 we established a xenograft model where TAM cells were transplanted into NOG mice to recapitulate the pathophysiology of TAM/ ML-DS. This xenograft model in combination with high-throughput genomic technology was used to show that genetically heterogeneous minor subclones with leukemia-initiating potential already exist in the neonatal TAM phase and could serve as initiating clones evolving to ML-DS in a patient.…”